Clinical Manifestation and Classification of Japanese Patients with Inherited Keratinizing Disorders

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1 Original Articles Juntendo Medical Journal (2), Clinical Manifestation and Classification of Japanese Patients with Inherited Keratinizing Disorders Aya k o IKEJIMA *1) Ya s u s h i SUGA * 1 )2 ) Yu k i MIZUNO * 1 )2 ) Ku n i t a k a HARUNA * 1 )2 ) K e n i c h i TANEDA *1) K a z u h i r o KOUROU * 1 )2 ) To s h i a k i SHIMIZU *3) Ta k a s h i YOSHIIKE *4) Hid e o k i OGAWA *1) Sh i g a k u IKEDA *1) Objective:Inherited keratinizing disorders are a spectrum of relatively rare skin diseases with a variety of congenital defects in the keratinizing process. In this study, we evaluated patients with inherited keratinizing disorders in the Tokyo urban area from the clinicians viewpoint. Patients:We retrospectively evaluated 77 cases of inherited keratinizing disorders(male/female:43/34 cases, mean age at first visit:20. 2 years)who visited our institution in the past 5 years. Methods:The cases were classified into 3 major groups; ichthyoses, palmoplantar keratodermas(ppk), and macular- and punctuate-type keratodermas. Definite diagnoses were achieved according to the clinico-pathological features and genetic analyses. Results:The ichthyoses group(48 cases:62. 3%)consisted of dominant ichthyosis vulgaris(iv:13 cases), X-linked ichthyosis(xli:16 cases), lamellar ichthyosis(li:4 cases), and bullous/nonbullous congenital ichthyosiform erythroderma(bcie and NBCIE:3 cases each). PPK groups(21 cases:27.3%)included Vörner-type(7 cases)and Nagashima-type(9 cases). Macular/punctuate-type keratodermas(8 cases:10. 4%)included 4 cases of Darier s disease. The discrepancy between percentages above and reported incidence of each disorder most likely resulted from the increasing tendency of visits in patients with severe symptoms. The therapeutic approach was application of topical moisturizers, in combination with topical vitamin D3 analogue, steroid, and antibiotics/antifungal agents. In addition, some cases were treated with oral retinoids and antihistamines. Conclusions:Although genetic analysis is necessary for definitive diagnosis, this simplified classification based on clinical features and morphological changes seems to be useful for clinical diagnosis and first-line aid for patients. The establishment of guidelines for diagnosis, therapy and patient care of inherited keratinizing disorders in Japan is urgently needed. Key words: inherited keratinizing disorders, congenital ichthyosis, congenital ichthyosiform erythroderma, ichthyosiform syndromes, palmoplantar keratoderma, Darier s disease. Introduction Inherited keratinizing disorders are a spectrum of relatively rare skin diseases with a variety of congenital defects in keratinizing process 1) 3). This group of disorders contains numerous numbers of disease entities and syndromes which present relatively lighter clinical symptoms to severe, lifethreatening conditions 4) 7). To date, the comprehensive survey of inherited keratinizing disorders has not been reported in Japanese population. Prior to nation-wide survey of these disorders, it is *1)Department of Dermatology, Juntendo University Faculty of Medicine, Tokyo, Japan *2)Department of Dermatology, Juntendo University Urayasu Hospital, Chiba, Japan *3)Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan *4)Department of Dermatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan Received June 13, 2011 Accepted July 28,

2 Ikejima et al:inherited keratinizing disorders in Japan Table 1 Proposed clinical classification of inherited keratinizing disorders Major groups Sub-groups Diseases Ichthyoses (Generalized, diffuse scale and hyperkeratosis) Severe forms A. with erythematic lesions B. without erythematic lesions Bullous congenital ichthyosiform erythroderma(bcie) Non-bullous congenital ichthyosiform erythroderma(nbcie) Mild forms Syndromes with complications of other organs Ichthyosis vulgaris(iv) X-linked ichthyosis(xli) Netherton syndrome Sjögren-Larsson syndrome Palmoplantar keratodermas(ppks; scale and hyperkeratosis in palmoplantar area) Diffuse type A. without transgrediens and progrediens, B. with transgrediens and progrediens) Localized(punctuate or linear) Syndromes comprising PPKs Vörner type Unna-Thost type Nagashima type Pachyonychia congenital Papillon-Lefevre syndrome Macular/punctate-type keratodermas Punctuate-type Macular-type Darier s disease Erythrokeratoderma variabilis(ekv) necessary to establish a systematic, clinical-based classification suitable for Japanese patients of inherited keratinizing disorders. In this study, therefore, we evaluated the patients of inherited keratinizing disorders using a simple clinical classification in a single center located in Tokyo urban area from the clinicians viewpoint. Subjects and Methods Patients profile and clinical classification In this study, we retrospectively analyzed a series of patients with inherited keratinizing disorders who visited the specialized outpatient clinic for keratinizing disorders, Department of Dermatology, Juntendo University Hospital, starting from 2001 to During this period, we diagnosed 77 patients of inherited keratinizing disorders; in which 76 cases(98.7%)were Japanese and the rest of one case(1.3%)was Italian. The patients comprised from 44 males and 33 females, and the mean age at the first visit was 20.2 year-old. For the first-step evaluation, we first classified the whole patient groups into 3 groups;ichthyoses, palmoplantar keratoderma(ppk), and the others including macular/punctuate-type keratoderma. Next, we sub-classified the ichthyoses and PPK groups with 4 and 3 categories, respectively, as follows(table 1). Ichthyoses group;1:severe forms with erythematic lesions, 2:severe forms without erythematic lesions, 3:mild forms, 4:ichthyosiform syndromes with complication of other organs. PPK group;1:diffuse type(a. without 136

3 Juntendo Medical Journal 58(2),2012 Table 2 Differential diagnosis Diseases Clinical features Pathology EM findings Biochemical assay/ihc Ichthyoses BCIE Blister formation PPKs Granular degeneration Abnormalities in tono-filament Gene mutations ( ) K1, K10 NBCIE # ( ) ( ) ( ) TGM1 * lipoxygenas * LI # ( ) Diminishing of marginal band TGase assay TGM1 HF Typical appearance ( ) Abnormalities ( ) ABCA12 in lamellar granule IV Family history * Palmoplantar keratosis Diminishing of the granular layer Abnormalities in keratohyaline * XLI Family history * ( ) ( ) Steroid sulfatase activity Netherton syndrome Vörner -type PPK Nagashima-type PPK Triad clubbing * Detachment of the horny layer * Granular degeneration Detachment of the horny layer * ( ) Profilaggrin Serine P activity IHC for LEKTI FISH analysis LEKTI Abnormalities ( ) K9, etc. in tono-filament Transgrediens, ( ) ( ) ( ) ( ) etc. * Others Darier s disease Multiple keratotic papules in seborrhetic area * Dyskeratosis Dyskeratosis ( ) ATP2A2 ;Definite findings, * :Important findings,#;additional findings,( );not useful for definite diagnosis transgrediens and progrediens, B. with transgrediens and progrediens), 2:localized(punctuate or linear), 3:syndromes complicated with PPK. In order to obtain the definite diagnosis, we performed pathological evaluations including electron micrography, and biochemical and genetic analyses for each patient. We made the final definitive diagnosis in combination with these parameters, the family tree analyses, and complications as diagnostic markers(table 2). For the genetic analysis, DNA sequencing for all exon and intermediate regions of exon-intron for every disease-committed sequence was performed, in cases who and/or whose family members(parents)gave informed consent in accordance with the institutional ethical committee for the clinical research(no. 111). The primer sets for the gene analyses were as described elsewhere 8) 11). The patients details, including the age at the first visit, gender, diagnositic process, and the current applications of topical and systemic therapeutics are demonstrated in Tables 3 5. In addition, we performed a questionnaire regarding the reason of visit to our specialized clinic. Results Clinical diagnosis and classification 1. Ichthyoses Our patient group included 6 cases of congenital ichthyosiform erythroderma;among these, 3 cases were diagnosed as bullous congenital ichthyosiform erythroderma(bcie)by clinical observations of bullous lesions, erosions and crust formation, in combination with pathological findings of granular degeneration observed under light and electron microscopy. The pathogenesis of this disorder involves dominant-negative mutation of differentiated-type keratin 1 and 10 12), and the mutations in 137

4 Ikejima et al:inherited keratinizing disorders in Japan Table 3 Patients distribution of disease types and gender differences Diseases Males Females Total Ichthyoses BCIE (62.3%) NBCIE LI HQ IV XLI Netherton syndrome Sjögren-Larsson syndrome subtotal PPKs Vörner-type PPK (27.3%) Nagashima-type PPK Pachyonychia Congenita KID syndrome Papillon-Lefevre syndrome subtotal Macular/punctuate keratoderma Darier s disease (10.4%) EKV CHILD syndrome subtotal Total Age at the first visit Ichthyoses PPKs Table 4 Age distribution at the first visit Macular/punctuate keratodermas Total cases % < Total Drugs Table 5 Topical and oral drug therapies Ichthyoses (total:41 cases) PPKs (21 cases) Macular- and punctuate-keratodermas (8 cases) Topical White petrolatum Urea ointment Heparinoid Petrolatum salicylate Vitamin D3 analogue Gluco-corticoids Antibiotics Antifungal agents Oral Etretinate Vitamin A Antihistamines

5 Juntendo Medical Journal 58(2),2012 keratin 2e has also been reported in patients with ichthyosis bullosa of Siemens 13). We have successfully detected the mutations in keratin genes in all of 3 cases, confirming the definite diagnosis. On the other hand, non-bullous congenital ichthyosiform erythroderma(nbcie)is considered as a complex of several diseases, and genetic mutations of lipoxigenese and transglutaminase(tgase)1 have been demonstrated in some cases of NBCIE 14). The rest of 3 cases of ichthyosiform erythroderma were diagnosed as NBCIE as a result of exceptional diagnosis, while no specific marker for diagnosis has been established. Our patient group contained 4 cases of lamellar ichthyosis(li), which was diagnosed based on the pathological findings of the thinner marginal zone and many lipid droplets in the horny layer by electron microscopy, and lower TGase 1 activity in situ detected using frozen sections of biopsy specimens. We also experienced one case of harlequin ichthyosis(hi)diagnosed by the extraordinary clinical manifestation at birth. Although compound heterozygous mutations of ABCA12 have recently been reported in a case of HI 15), we had not determined the genetic mutation of our case at diagnosis. We diagnosed 16 cases of X-linked ichthyosis (XLI)using diagnostic markers such as low activities of leukocyte steroid sulfatase 16), and detection of the genetic defect using FISH probe and PCR analysis. On the other hand, ichthyosis vulgaris(iv)typically demonstrates the diminishing of the granular layer, which is observed under light and electron microscopy. We diagnosed 13 cases of IV based on the clinical/histological manifestations of follicular keratosis, palmoplantar keratosis in combination with the differential diagnosis of XLI(Table 2). In addition, ichthyosiform syndromes, which are characterized as keratodermas with complications of other organs, were diagnosed by their typical combination of extra-dermal disorders. We diagnosed 7 cases of Netherton syndrome, which expressed abnormalities in hair and atopic dermatitis, and one case of Sjögren-Larsson syndrome, which is complicated with spastic paralysis. 2. Palmoplantar keratdermas Diffuse types of palmoplantar keratodermas (PPKs), which are characterized as diffuse keratotic lesions with reddish edges in the palms and plantar regions, were sub-classified into Vörner and Unna-Thost types. We diagnosed 7 cases of Vörner-type PPK by pathological findings of epidermolytic diffuse PPK with granular degeneration. Our patient group did not include Unna- Thost-type, which shows non-epidermolytic PPK. On the other hand, Nagashima-type PPK, which expresses trasgrediens and progrediens, typically demonstrates diffuse, light keratoderma with eruptions in the dorsum of hand and foot, elbow and knee. We diagnosed 9 cases of Nagashima-type PPK, by differential diagnoses from mal de Meleda, which expresses heavier symptoms, and Greither type PPK, which is autosomal dominant and demonstrates progressive skin lesions extensive to forearms and lower legs. In addition, we experienced 3 cases of pachyonychia congenita, which expresses thickening of nails in combination with coated tongue, and one case of keratitis-ichthyosis-deafness(kid)syndrome, who was indeed complicated with keratitis and deafness. 3. Macular and punctuate and keratoderma We diagnosed 4 patients with Darier s disease from clinical manifestations comprising punctuate, keratotic eruptions in seborrhetic areas, pitting of palms, and nail lesions, in combination with pathological findings of dyskeratosis. We also diagnosed 3 cases of erhythrokeratoderma variabilis(ekv) with its typical clinical findings. Clinical features of inherited keratinizing disorders in Japan 1. Proportion of disease types As shown in Table 3, the cases were classified into groups of ichthyosis(48 cases;62. 3%), PPK(21 cases;27. 3%), and macular/punctuate keratoderma(8 cases;10.4%). With simplified classification, ichthyosis group patients were divided into 6 and 5 cases of severe diseases with and without erythematic lesions, respectively, 29 cases of mild diseases, and 8 cases of ichthyosis syndromes(table 3). Ichthyosis group consisted of dominant ichthyosis vulgaris(iv;13 cases), X-linked ichthyosis(xli;16 cases), lamellar ichthyosis(li;4 cases), and bullous/nonbullous congenital ichthyosiform erythroderma(3 cases each). PPKs group included Vörner-type(7 cases)and Nagashima-type(9 cases), and macular/punctuate kerato- 139

6 Ikejima et al:inherited keratinizing disorders in Japan dermas included 4 cases of Darier s disease. The discrepancy between percentages above and reported incidence of each disorder most likely resulted from the increasing tendency of visits in patients with severe symptoms. 2. Gender difference In this study, the total numbers of male and female patients were 43 and 34 cases, respectively, and the gender proportion in the all patient group was 1.3:1.0(male vs. female). Among a variety of subgroups, female patients of IV were almost 3-fold more than male patients(male:3 cases, female:10 cases), indicating obvious female dominance. On the other hand, all patients with XLI were indeed males. 3. Age distribution The distribution of age at the first visit was documented in Table 4. The age at the first visit ranged from 0 to 81 years-old, and the mean age was 20.2 year-old. Interestingly, the age distribution demonstrated two peaks at the early ages from 0 to 5 years-old and middle ages from 30 to 40 years-old. It is quite natural that nearly 1/4 of the patients were ranged from 0 to 5 years-old. In addition, increased number of patients was observed between 30 to 40 years-old, which includes 4 cases of consultation for inheritance and 3 cases of uncontrollable diseases after adolescent period. Further, 4 cases of adult-onset Darier s disease were included in macular- and punctuate-keratoderma at the ranges between 20 to 40 years-old. 4. Treatment The basis of therapeutic approach remains with topical moisturizers, in combination with topical vitamine D3, steroid, and antibiotics/antifungal agents. As shown in Table 5, over 60% of patients were treated using topical moisturizers and keratolytic agents, based on the disease types and the pathophysiological defects in barrier functions. Specifically, moisturizers including white petrolatum(vaseline)appear to be useful in patients with LI, NBCIE, and Netherton syndrome, in which the horny layer were dried and thickened with proliferation of epidermis. On the other hand, the keratolytic agents, such as urea lotion and petrolatum salicylate, seem to be appropriate in patients with IV and XLI, where retention of the excessive horny layer due hyperkeratosis most likely play a major role. Since long-term treatment is required for the patients with inherited keratinizing disorders, it is important of select the therapeutics with high efficacy and safety with consideration of compliance. Further, the cost evaluation of the therapeutic options is also important since governmental support only covers chronic diseases in childhood. In addition, adverse effects of topical drugs caused by over-absorption via the damaged skin, since contact and irritant dermatitis often superimposes inherited keratinizing disorders. In addition, some cases were treated with oral retinoids. Among these patients, only 4 patients among 41 total cases of ichthyoses were received etretinate, which has considerable adverse effects. Instead, 5 cases of ichthyoses and 3 cases of PPKs were given oral vitamin A, which has fewer side effects. Oral medication was applied especially to the patients whose symptoms were not relieved with prolonged topical therapies. Anti-allergic and anti-histamine drugs were predominantly used in the cases with worsening of urticaria-like edematous erythema, and prevention of scratching for itchy skin lesions. 5. Reasons for specialized outpatient clinic Since increasing number of patients visited our specialized outpatient clinic for keratinizing disorders by referral from other institutions and practitioners, we performed the questionnaire regarding to the merits for the visit. Among the high-rated answers, the patients raised the advantage points as follows, 1. Appropriate diagnosis, disease explanation and consultation for inheritance based on the updated information. 2. Total care in the general hospital with multiple departments. 3. Intensive patient care by specialists for keratinizing disorders. 4. Active linkage from children hospitals to special dermatologists. Discussion To date, numerous types of inherited keratinizing disorders have been reported worldwide, while the definite diagnosis of each disorder usually requires complicated process. This complexity has avoided the nation-wide survey of these relatively rare disorders in Japan. Although the precise description of each disorder was available in conventional textbooks of dermatology, a systematic clinical classification suitable for Japanese patients of inherited keratinizing disorders has not been es- 140

7 Juntendo Medical Journal 58(2),2012 tablished. From this point of view, here we tried to establish a new, simple classification of inherited keratinizing disorders, and performed a pilot survey in a single institution located in Tokyo urban area. In terms of diagnostic procedure for inherited keratinizing disorders, the simplified classification based on clinical and morphological features appears to be useful for evaluation of severity and prognosis of individual cases, and decision in therapeutic strategies. In addition, this classification is also important for cumulative evaluation of clinical cases. For the final diagnosis of each case, combination of clinico-pathological features and biochemical and genetic analyses are required(figure 2 ). In some instance, however, the delay of diagnosis using gene analysis may result in unfavorable and untimely correspondence to the patients. To avoid this possibility, it is necessary to establish a diagnositic algorithm based on clinico-pathological features. At the current moment, Japanese Dermatological Association has only released a practical guideline for BCIE 17). It is required to establish a guideline for diagnosis, therapy and patient care of the whole spectrum of inherited keratinizing disorders in Japan. In this study, we evaluated the proportion of disease types in inherited keratinizing disorders in our facility. Here, the numbers of IV and BCIE patients were not different, whereas the reported incidences of these diseases are 1/200 and less than 1/100,000, respectively 18)19). The discrepancy in proportion is in part explained by the fact that patients with severe symptoms and/or the rare disorders tend to visit our specialized outpatient clinic in the university hospital. In addition, the proportion of PPK appears to be higher in rate as compared to the reported incidence of this disease, probably because of uncontrollable symptoms in hands and feet, where the skin lesions are easy to worsen by a variety of irritants. On the other hand, we had relatively small numbers of cases for IV and XLI, which develop mild symptoms therefore the patients tend to receive medical care in the local clinics/hospitals rather than university hospitals. In conclusion, this simplified classification of inherited keratinizing disorders based on clinical features and morphological changes seems to be useful for clinical diagnosis and the first-line aid for the patients, while genetic analysis is necessary for the definite diagnosis. It is necessary to establish a practical guideline for the whole spectrum of inherited keratinizing disorders in Japan, which would facilitate the easy diagnosis and systematic treatment/patient care even in the local facilities. In the outpatient clinic in the university hospital, on the other hand, precise molecular diagnosis and individualized treatment/patient care based on the updated information should be provided by the expert dermatologists in corroboration with doctors of other specialties. Acknowledgement The classification of inherited ichthyosis described in this study is different from that of a new classification based on molecular genetics proposed at the 2009 Ichthyosis Consensus Conference on the terminology and classification of inherited ichthyoses in Sorèze, France 20)21), because our study had been carried out prior to this meeting. References 1)Braun-Falco O, Plewig G, Wolff HH, et al:keratoses. In:Dermatology. Berlin:Springer-Verlag, 1991;511~ )Judge MR, McLean WHI, Munro CS:Disorders of Keratinization. In:Bruns T, Breathnach S, Cox N, et al, eds. Rook s Textbook of Dermatology. Volume 2. 7th ed. Malden:Blackwell Publishing, Inc., 2004;1~105. 3)Shwayder T:Disorders of keratinization:diagnosis and management. Am J Clin Dermatol, 2004;5:17~ 29. 4)DiGiovanna JJ:Ichthyosiform Dermatoses. In:Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick s Dermatology in General Medicine. Volume 1. 6th ed. New York:McGraw-Hill, 2003;481~505. 5)Stevens HP, Kelsell DP, Leigh IM:The inherited keratodermas of palms and soles. In:Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick s Dermatology in General Medicine. Volume 1. 6th ed. New York: McGraw-Hill, 2003;505~514. 6)Goldsmith LA, Baden HP:Darier-White disease(keratosis follicularis)and acrokeratosis verruciformis. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick s Dermatology in General Medicine. Volume 1. 6th ed. New York:McGraw-Hill, 2003;523~528. 7)Yoshiike T, Ogawa H:Standard classification from clinical aspect. In:Ogawa H, Nagashima M, Ishibashi Y, ed. The color atlas of "disorders of keratinization". Tokyo: Kyowa Kikaku, 2003;vi~x. 8)Smith FJ, Maingi C, Covello SP, et al:genomic organization and fine mapping of the keratin 2e gene (KRT2E):K2e V1 domain polymorphism and novel mutations in ichthyosis bullosa of Siemens. J Invest Dermatol, 1998;111:817~821. 9)Sun XK, Ma LL, Xie YQ, et al:keratin 1 and keratin

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