Baty, D.

Lamb, R. C.

Lang, J.

McLean, W. H. I.

Terron-Kwiatowski, A.

Zamiri, M.

PubMed

R.C. Lamb

J. Lang

A. Terron‐Kwiatowski

D. Baty

W.H.I. McLean

M. Zamiri

Crossref

British Journal of Dermatology

Avascular necrosis of the hip and diffuse idiopathic skeletal hyperostosis during long‐term isotretinoin treatment of epidermolytic ichthyosis due to a novel deletion mutation in
            <scp>
              <i>KRT10</i>
            </scp>

Discovery Research Portal

                                                                    University of DundeeAvascular necrosis of the hip and diffuse idiopathic skeletal hyperostosis during long-term isotretinoin treatment of epidermolytic ichthyosis due to a novel deletionmutation in KRT10Lamb, R. C.; Lang, J.; Terron-Kwiatowski, A.; Baty, D.; McLean, W. H. I.; Zamiri, M.Published in:British Journal of DermatologyDOI:10.1111/bjd.13049Publication date:2014Document VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Lamb, R. C., Lang, J., Terron-Kwiatowski, A., Baty, D., McLean, W. H. I., & Zamiri, M. (2014). Avascularnecrosis of the hip and diffuse idiopathic skeletal hyperostosis during long-term isotretinoin treatment ofepidermolytic ichthyosis due to a novel deletion mutation in KRT10. British Journal of Dermatology, 171(4), 913-915. https://doi.org/10.1111/bjd.13049General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 24. Dec. 20196 Ghoshal UC, Ghoshal U, Jain M et al. Strongyloides stercoralis infesta-tion associated with septicemia due to intestinal transmural migra-tion of bacteria. J Gastroenterol Hepatol 2002; 17:1331–3.7 Newberry AM, Williams DN, Stauffer WN et al. Strongyloides hyper-infection presenting as acute respiratory failure and gram-negativesepsis. Chest 2005; 128:3681–4.8 Buonfrate D, Requena-Mendez A, Angheben A et al. Severe stron-gyloidiasis: a systematic review of case reports. BMC Infect Dis2013; 13:78.9 Corsini AC. Strongyloidiasis and chronic urticaria. Postgrad Med J1982; 58:247–8.10 Asato R. [Result report of the project for control of the endemicinfection (Strongyloides Stercoralis) in Okinawa prefecture (1987–1992)]. Infect Agents Surveillance Rep 1993; 14:158 (in Japanese).Funding sources: none.Conflicts of interest: none declared.Avascular necrosis of the hip and diffuseidiopathic skeletal hyperostosis during long-term isotretinoin treatment of epidermolyticichthyosis due to a novel deletion mutation inKRT10DOI: 10.1111/bjd.13049DEAR EDITOR, Epidermolytic ichthyosis (EI; OMIM 113800),previously termed bullous congenital ichthyosiform erythro-derma or epidermolytic hyperkeratosis, is a clinically heteroge-neous disorder of keratinization. It is usually characterized bysevere neonatal erythroderma, blistering and fragile skin, withthe subsequent development of hyperkeratosis, predominantlyin flexural areas. It is caused by mutations in either the KRT1or KRT10 genes encoding the suprabasal keratins K1 and K10,respectively.1 Mutations are usually missense substitutions inthe highly conserved alpha-helical rod domains of these kera-tins, which play a critical role in filament formation.2 Wereport a multigeneration kindred with EI due to a novel muta-tion in KRT10.The proband was a 32-year-old woman from Shetland.She presented with widespread fine scale and erythema ofher trunk and limbs, with a history of scaling and rednesssince birth but no blistering, erosions or collodion mem-brane reported. Clinical examination revealed widespread ich-thyosis and erythema affecting the trunk and all four limbs,with more significant hyperkeratosis at the elbows, kneesand ankles but relative sparing of palmoplantar skin (Fig. 1).Her father, uncle and grandmother were affected, and fourfurther generations were reported to be affected. She hadbeen maintained on oral isotretinoin 20–40 mg daily, thusmodifying the clinical appearance, from the age of 13 years,but had recently developed lower back and hip pain. Radio-graphs of the lumbar spine and left hip demonstrated bridg-ing osteophytes form T11 to L1, suggestive of diffuseidiopathic skeletal hyperostosis (DISH), and magnetic reso-nance imaging confirmed the presence of avascular necrosisof the left hip. This was successfully treated with coredecompression of the left hip with improvement in thepatient’s pain.A biopsy of affected skin of the upper limb was obtainedfrom the proband and processed for light microscopy by stan-dard methods. Structural analysis demonstrated acanthosis,marked overlying hyperkeratosis and vacuolar change of theupper epidermal cells with prominent clumping of keratohya-line granules.Following informed consent, genomic DNA samples wereobtained from blood samples from the proband and herfather. Mutation analysis of the coding regions and splice sitesof the KRT1 and KRT10 genes was performed by standard poly-merase chain reaction (PCR) and Sanger sequencing methodsusing specific primers. Sequence analysis of KRT10 revealed apreviously unreported heterozygous deletion of 167 base pairsextending from intron 5 into exon 6 (c.1156–79_1243del),abolishing the intron 5 acceptor splice site (Fig. 2). Thismutation was also present in the proband’s affected father.(a)(b)(c)Fig 1. Family with epidermolytic ichthyosis. (a) Clinical picture ofthe proband: hyperkeratosis of nonplantar sites modified by oralretinoid therapy; (b, c) photographs of her father.Correspondence 913© 2014 The Authors. British Journal of Dermatologypublished by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.This is an open access article under the terms of the Creative Commons Attribution License, which permits use,distribution and reproduction in any medium, provided the original work is properly cited.British Journal of Dermatology (2014) 171, pp903–920RNA was obtained from the proband’s skin biopsy. Follow-ing reverse transcription by standard methods, reverse-trans-criptase PCR was performed using primers flanking thedeletion on exons 5 and 6 of KRT10. RNA analysis demon-strated that the KRT10 c.1156–79_1243del deletion activates acryptic splice site 96 base pairs downstream from the consen-sus intron 5–exon 6 splice site, resulting in an in-frame dele-tion of 32 amino acids, p.Lys386_Gln417, in the K10 protein.This truncated K10 protein, lacking the conserved helix termi-nation motif, is likely to exert a dominant–negative effect onK1/K10 filament formation.The keratin intermediate filament network is the mainstress-bearing structure within the cytoplasm of epithelialcells. EI is caused by mutations in the keratin genes KRT1 andKRT10, which confer structural integrity to suprabasal kerati-nocytes, with most reported mutations being heterozygousmissense mutations.3 Approximately half of all cases of EIoccur sporadically due to a spontaneous mutation.2 In inher-ited cases of EI, it is inherited mostly in a dominant mode,as in this pedigree, although recessive inheritance has beenreported.4 Severe EI has been associated with mutations inthe highly conserved helix boundary motifs, the helix initia-tion and termination peptides and the nonhelical H1 domainof K1 and K10.3 Mutations in the L1–2 linker of K1 or out-side the helix boundary motifs, similar to those seen in mildepidermolysis bullosa simplex, have been described.5 A smallnumber of insertion/deletion mutations and splice-site defectsleading to larger in-frame deletions or rare dinucleotide alter-ations in KRT10, leading to substitution of two adjacentamino acids, have been described.6 Genotype–phenotype cor-relations in EI are very complex, and it is suggested that boththe position of the mutation within K1 or K10 and the nat-ure of the amino acid substitution specifically influence thephenotypic expression of the disease.7 Systemic retinoidsshould be used with caution in EI due to a risk of increasedfragility and a tendency to blistering, although both topicaland oral retinoids are thought to be more effective in thosepatients with EI with K10 mutations compared with K1. It ispostulated that this may be due to the ability of patients withK10 mutations to tolerate better the downregulation of K2caused by retinoids.8To our knowledge, avascular necrosis of the femoral headhas not previously been reported secondary to isotretinoin,and it is unclear whether this contributed to the findings inthe proband. Avascular necrosis of the femoral head occursdue to interruption of the microcirculation of the femoralhead resulting in ischaemia, and may occur spontaneously orin relation to treatment with glucocorticoids, hypertension,sickle cell disease, trauma or other causes. Avascular necrosisof the hip has been reported with retinoids (all-trans-retinoicacid) used to treat haematological conditions; however,affected cases have often received concomitant glucocortic-oids.9 The long-term effects of oral retinoids remain underdebate; however, experience of exposure to isotretinoin at thisdose and for this length of time has been reported in the liter-ature only rarely in comparison with other retinoids.10 Previ-ously reported skeletal abnormalities with retinoid therapyinclude periosteal thickening, premature epiphyseal closure inchildren, osteoporosis, extraspinal tendon and ligament calcifi-cation, osteophytes and bony bridges between vertebrae as inthe proband, in addition to DISH characterized by anteriorspinal ligament calcification. However, there are few prospec-tive studies on the skeletal effects of long-term systemic reti-noids, and many of the bony changes reported are alsoprevalent in the general population. This finding adds to theevidence that KRT10 mutations are the principal cause of auto-somal dominant EI with palmoplantar sparing. It also high-lights the possible side-effects of long-term oral retinoidtreatment in these inherited conditions.AcknowledgmentsWe would like to thank the patients, their family membersand control subjects for their cooperation in this study.R .C . LAMB1J . LANG2A . TERRON-KWIATOWSK I 3D. BATY3W.H. I . MCLEAN4M. ZAM I R I 1 , 51Department of Dermatology, and2Department of Pathology, UniversityHospital Crosshouse, Kilmarnock, U.K.3East of Scotland Genetics Service, NinewellsHospital, Dundee, U.K.4Centre for Dermatology and GeneticMedicine, Division of Molecular Medicine,University of Dundee, Dundee, U.K.5Alan Lyell Centre for Dermatology,Glasgow, U.K.E-mail: rlamb@nhs.netFig 2. DNA sequencing of the KRT10 gene in the proband. Sequencing reveals a novel heterozygous deletion extending from intron 5 into exon 6(K10 c.1156–79_1243del), abolishing the exon 6 acceptor splice site resulting in a shorter aberrant keratin 10 (K10) protein lacking a sequencemotif critically important for keratin filament assembly. The mutation was present in the proband’s affected father but not in unaffected controlsamples.914 Correspondence© 2014 The Authors. British Journal of Dermatologypublished by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.British Journal of Dermatology (2014) 171, pp903–920References1 Oji V, Tadini G, Akiyama M et al. Revised nomenclature and classi-fication of inherited ichthyoses: results of the First Ichthyosis Con-sensus Conference in Soreze 2009. J Am Acad Dermatol 2010;63:607–41.2 Irvine AD, McLean WHI. Human keratin diseases: the increasingspectrum of disease and subtlety of the phenotype–genotype cor-relation. Br J Dermatol 1999; 140:815–28.3 Lane EB, McLean WHI. Keratins and skin disorders. J Pathol 2004;204:355–66.4 Covaciu C, Castori M, De Luca N et al. Lethal autosomal recessiveepidermolytic ichthyosis due to a novel donor splice site mutationin KRT10. Br J Dermatol 2010; 162:1384–7.5 Bolling MC, Bladergroen RS, van Steensal MA et al. A novel muta-tion in the L12 domain of keratin 1 is associated with mild epi-dermolytic ichthyosis. Br J Dermatol 2010; 162:875–9.6 Szeverenyi I, Cassidy AJ, Chung CW et al. The human intermedi-ate filament database: comprehensive information on a gene fam-ily involved in many human diseases. Hum Mutat 2008; 29:351–60.7 Arin MJ, Oji V, Emmert S et al. Expanding the keratin mutationdatabase: novel and recurrent mutations and genotype–phenotypecorrelations in 28 patients with epidermolytic ichthyosis. Br J Der-matol 2011; 164:442–7.8 Vahlquist A, Ganemo A, Virtanen M. Congenital ichthyosis: anoverview of current and emerging therapies. Acta Derm Venereol2008; 88:4–14.9 Sakakura M, Nishii K, Usui E et al. Bilateral osteonecrosis of thehead of the femur during treatment with retinoic acid in a youngpatient with acute promyelocytic leukemia. Int J Hematol 2006;83:252–3.10 Ellis CN, Pennes DR, Hermann RC et al. Long-term radiographicfollow-up after isotretinoin therapy. J Am Acad Dermatol 1988; 18:1252–61.Funding sources: The Centre for Dermatology and Genetic Medicine atthe University of Dundee is supported by a Wellcome Trust StrategicAward (098439/Z/12/Z to W.H.I.M.).Conflicts of interest: None declared.Short- to intermediate-term follow-up inpatients treated with the combination of311-nm ultraviolet B phototherapy andbiological agentsDOI: 10.1111/bjd.12992DEAR EDITOR, Previous studies1–4 have indicated that ultraviolet(UV) B phototherapy may increase the therapeutic response tobiologics (see also citations in refs 1–4). Most recently, Cal-zavara-Pinton et al. reported that combined treatment with311-nm UVB and etanercept had a synergistic effect for clear-ing chronic plaque-type psoriasis that was previously un-responsive to either form of monotherapy alone.5 However,UVB phototherapy is potentially carcinogenic (although thishas not yet been shown for 311-nm UVB in humans), andthere are safety concerns, particularly in combination withbiological agents.4 We therefore analysed all available follow-up data to detect nonmelanoma skin cancer (NMSC) or mela-noma in patients with psoriasis treated with 311-nm UVBphototherapy in combination with various biologics in differ-ent trials at our institution.1–4From 29 patients with chronic plaque psoriasis who hadbeen treated by combining 311-nm UVB with at least onebiological agent at our department,1–4 28 (10 women, 18men) were included in the follow-up analysis. One patientwas excluded from the risk analysis because of a history of mul-tiple grenz (Bucky) X-ray irradiation-related basal cell carcino-mas before the start of combination treatment, but wasincluded in the statistical analysis of therapeutic efficacyshown in Table 1. One patient, who was discontinued fromthe half-body comparison study with ustekinumab4 because ofa circumscribed herpetic eruption on the thigh on the UV-exposed body half, was excluded from the statistical analysisTable 1 Results on the efficacy of 311-nm ultraviolet (UV) B plus biologic combination therapyBiologic, ref./NCT no.Numberof patientstreated ina studyPercentage PASI reductionWeek 6 Week 12UV No UV UV No UVEtanercept3 5 850 552 907 810Adalimumab2, NCT00638469 6 835 461 677 512GolimumabNCT01088698 2 829 693 n.a. n.a.Ustekinumab4 9 816 541 846 789Alefacept1 14 726 315 827 637All biological agents 36a 811 512* 814 687†Data are mean values calculated from the results of 311-nm UVB half-side comparison studies, previously reported in refs 1–4 and two regis-tered clinical trials. PASI, Psoriasis Area and Severity Index; n.a., not available. aCertain patients participated in more than one trial; thereforethe total number for treatment with biological agents is higher than the total patient number (i.e. 28). *P = 0003; †P = 00255 by two-tailed paired Student’s t-test comparing the UV-irradiated body halves vs. the nonirradiated body halves, based on intention to treat as in thefirst 6 weeks. Note that a portion of the patients (n = 6) were also treated between weeks 7 and 12 with total-body 311-nm UVB (includingthe previously nonirradiated body half).© 2014 British Association of Dermatologists British Journal of Dermatology (2014) 171, pp903–920Correspondence 915

Avascular necrosis of the hip and diffuse idiopathic skeletal hyperostosis during long-term isotretinoin treatment of epidermolytic ichthyosis due to a novel deletion mutation in KRT10

                                                                    University of DundeeAvascular necrosis of the hip and diffuse idiopathic skeletal hyperostosis during long-term isotretinoin treatment of epidermolytic ichthyosis due to a novel deletionmutation in KRT10Lamb, R. C.; Lang, J.; Terron-Kwiatowski, A.; Baty, D.; McLean, W. H. I.; Zamiri, M.Published in:British Journal of DermatologyDOI:10.1111/bjd.13049Publication date:2014Licence:CC BYDocument VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Lamb, R. C., Lang, J., Terron-Kwiatowski, A., Baty, D., McLean, W. H. I., & Zamiri, M. (2014). Avascularnecrosis of the hip and diffuse idiopathic skeletal hyperostosis during long-term isotretinoin treatment ofepidermolytic ichthyosis due to a novel deletion mutation in KRT10. British Journal of Dermatology, 171(4), 913-915. https://doi.org/10.1111/bjd.13049General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 17. Aug. 20236 Ghoshal UC, Ghoshal U, Jain M et al. Strongyloides stercoralis infesta-tion associated with septicemia due to intestinal transmural migra-tion of bacteria. J Gastroenterol Hepatol 2002; 17:1331–3.7 Newberry AM, Williams DN, Stauffer WN et al. Strongyloides hyper-infection presenting as acute respiratory failure and gram-negativesepsis. Chest 2005; 128:3681–4.8 Buonfrate D, Requena-Mendez A, Angheben A et al. Severe stron-gyloidiasis: a systematic review of case reports. BMC Infect Dis2013; 13:78.9 Corsini AC. Strongyloidiasis and chronic urticaria. Postgrad Med J1982; 58:247–8.10 Asato R. [Result report of the project for control of the endemicinfection (Strongyloides Stercoralis) in Okinawa prefecture (1987–1992)]. Infect Agents Surveillance Rep 1993; 14:158 (in Japanese).Funding sources: none.Conflicts of interest: none declared.Avascular necrosis of the hip and diffuseidiopathic skeletal hyperostosis during long-term isotretinoin treatment of epidermolyticichthyosis due to a novel deletion mutation inKRT10DOI: 10.1111/bjd.13049DEAR EDITOR, Epidermolytic ichthyosis (EI; OMIM 113800),previously termed bullous congenital ichthyosiform erythro-derma or epidermolytic hyperkeratosis, is a clinically heteroge-neous disorder of keratinization. It is usually characterized bysevere neonatal erythroderma, blistering and fragile skin, withthe subsequent development of hyperkeratosis, predominantlyin flexural areas. It is caused by mutations in either the KRT1or KRT10 genes encoding the suprabasal keratins K1 and K10,respectively.1 Mutations are usually missense substitutions inthe highly conserved alpha-helical rod domains of these kera-tins, which play a critical role in filament formation.2 Wereport a multigeneration kindred with EI due to a novel muta-tion in KRT10.The proband was a 32-year-old woman from Shetland.She presented with widespread fine scale and erythema ofher trunk and limbs, with a history of scaling and rednesssince birth but no blistering, erosions or collodion mem-brane reported. Clinical examination revealed widespread ich-thyosis and erythema affecting the trunk and all four limbs,with more significant hyperkeratosis at the elbows, kneesand ankles but relative sparing of palmoplantar skin (Fig. 1).Her father, uncle and grandmother were affected, and fourfurther generations were reported to be affected. She hadbeen maintained on oral isotretinoin 20–40 mg daily, thusmodifying the clinical appearance, from the age of 13 years,but had recently developed lower back and hip pain. Radio-graphs of the lumbar spine and left hip demonstrated bridg-ing osteophytes form T11 to L1, suggestive of diffuseidiopathic skeletal hyperostosis (DISH), and magnetic reso-nance imaging confirmed the presence of avascular necrosisof the left hip. This was successfully treated with coredecompression of the left hip with improvement in thepatient’s pain.A biopsy of affected skin of the upper limb was obtainedfrom the proband and processed for light microscopy by stan-dard methods. Structural analysis demonstrated acanthosis,marked overlying hyperkeratosis and vacuolar change of theupper epidermal cells with prominent clumping of keratohya-line granules.Following informed consent, genomic DNA samples wereobtained from blood samples from the proband and herfather. Mutation analysis of the coding regions and splice sitesof the KRT1 and KRT10 genes was performed by standard poly-merase chain reaction (PCR) and Sanger sequencing methodsusing specific primers. Sequence analysis of KRT10 revealed apreviously unreported heterozygous deletion of 167 base pairsextending from intron 5 into exon 6 (c.1156–79_1243del),abolishing the intron 5 acceptor splice site (Fig. 2). Thismutation was also present in the proband’s affected father.(a)(b)(c)Fig 1. Family with epidermolytic ichthyosis. (a) Clinical picture ofthe proband: hyperkeratosis of nonplantar sites modified by oralretinoid therapy; (b, c) photographs of her father.Correspondence 913© 2014 The Authors. British Journal of Dermatologypublished by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.This is an open access article under the terms of the Creative Commons Attribution License, which permits use,distribution and reproduction in any medium, provided the original work is properly cited.British Journal of Dermatology (2014) 171, pp903–920RNA was obtained from the proband’s skin biopsy. Follow-ing reverse transcription by standard methods, reverse-trans-criptase PCR was performed using primers flanking thedeletion on exons 5 and 6 of KRT10. RNA analysis demon-strated that the KRT10 c.1156–79_1243del deletion activates acryptic splice site 96 base pairs downstream from the consen-sus intron 5–exon 6 splice site, resulting in an in-frame dele-tion of 32 amino acids, p.Lys386_Gln417, in the K10 protein.This truncated K10 protein, lacking the conserved helix termi-nation motif, is likely to exert a dominant–negative effect onK1/K10 filament formation.The keratin intermediate filament network is the mainstress-bearing structure within the cytoplasm of epithelialcells. EI is caused by mutations in the keratin genes KRT1 andKRT10, which confer structural integrity to suprabasal kerati-nocytes, with most reported mutations being heterozygousmissense mutations.3 Approximately half of all cases of EIoccur sporadically due to a spontaneous mutation.2 In inher-ited cases of EI, it is inherited mostly in a dominant mode,as in this pedigree, although recessive inheritance has beenreported.4 Severe EI has been associated with mutations inthe highly conserved helix boundary motifs, the helix initia-tion and termination peptides and the nonhelical H1 domainof K1 and K10.3 Mutations in the L1–2 linker of K1 or out-side the helix boundary motifs, similar to those seen in mildepidermolysis bullosa simplex, have been described.5 A smallnumber of insertion/deletion mutations and splice-site defectsleading to larger in-frame deletions or rare dinucleotide alter-ations in KRT10, leading to substitution of two adjacentamino acids, have been described.6 Genotype–phenotype cor-relations in EI are very complex, and it is suggested that boththe position of the mutation within K1 or K10 and the nat-ure of the amino acid substitution specifically influence thephenotypic expression of the disease.7 Systemic retinoidsshould be used with caution in EI due to a risk of increasedfragility and a tendency to blistering, although both topicaland oral retinoids are thought to be more effective in thosepatients with EI with K10 mutations compared with K1. It ispostulated that this may be due to the ability of patients withK10 mutations to tolerate better the downregulation of K2caused by retinoids.8To our knowledge, avascular necrosis of the femoral headhas not previously been reported secondary to isotretinoin,and it is unclear whether this contributed to the findings inthe proband. Avascular necrosis of the femoral head occursdue to interruption of the microcirculation of the femoralhead resulting in ischaemia, and may occur spontaneously orin relation to treatment with glucocorticoids, hypertension,sickle cell disease, trauma or other causes. Avascular necrosisof the hip has been reported with retinoids (all-trans-retinoicacid) used to treat haematological conditions; however,affected cases have often received concomitant glucocortic-oids.9 The long-term effects of oral retinoids remain underdebate; however, experience of exposure to isotretinoin at thisdose and for this length of time has been reported in the liter-ature only rarely in comparison with other retinoids.10 Previ-ously reported skeletal abnormalities with retinoid therapyinclude periosteal thickening, premature epiphyseal closure inchildren, osteoporosis, extraspinal tendon and ligament calcifi-cation, osteophytes and bony bridges between vertebrae as inthe proband, in addition to DISH characterized by anteriorspinal ligament calcification. However, there are few prospec-tive studies on the skeletal effects of long-term systemic reti-noids, and many of the bony changes reported are alsoprevalent in the general population. This finding adds to theevidence that KRT10 mutations are the principal cause of auto-somal dominant EI with palmoplantar sparing. It also high-lights the possible side-effects of long-term oral retinoidtreatment in these inherited conditions.AcknowledgmentsWe would like to thank the patients, their family membersand control subjects for their cooperation in this study.R .C . LAMB1J . LANG2A . TERRON-KWIATOWSK I 3D. BATY3W.H. I . MCLEAN4M. ZAM I R I 1 , 51Department of Dermatology, and2Department of Pathology, UniversityHospital Crosshouse, Kilmarnock, U.K.3East of Scotland Genetics Service, NinewellsHospital, Dundee, U.K.4Centre for Dermatology and GeneticMedicine, Division of Molecular Medicine,University of Dundee, Dundee, U.K.5Alan Lyell Centre for Dermatology,Glasgow, U.K.E-mail: rlamb@nhs.netFig 2. DNA sequencing of the KRT10 gene in the proband. Sequencing reveals a novel heterozygous deletion extending from intron 5 into exon 6(K10 c.1156–79_1243del), abolishing the exon 6 acceptor splice site resulting in a shorter aberrant keratin 10 (K10) protein lacking a sequencemotif critically important for keratin filament assembly. The mutation was present in the proband’s affected father but not in unaffected controlsamples.914 Correspondence© 2014 The Authors. British Journal of Dermatologypublished by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.British Journal of Dermatology (2014) 171, pp903–920References1 Oji V, Tadini G, Akiyama M et al. Revised nomenclature and classi-fication of inherited ichthyoses: results of the First Ichthyosis Con-sensus Conference in Soreze 2009. J Am Acad Dermatol 2010;63:607–41.2 Irvine AD, McLean WHI. Human keratin diseases: the increasingspectrum of disease and subtlety of the phenotype–genotype cor-relation. Br J Dermatol 1999; 140:815–28.3 Lane EB, McLean WHI. Keratins and skin disorders. J Pathol 2004;204:355–66.4 Covaciu C, Castori M, De Luca N et al. Lethal autosomal recessiveepidermolytic ichthyosis due to a novel donor splice site mutationin KRT10. Br J Dermatol 2010; 162:1384–7.5 Bolling MC, Bladergroen RS, van Steensal MA et al. A novel muta-tion in the L12 domain of keratin 1 is associated with mild epi-dermolytic ichthyosis. Br J Dermatol 2010; 162:875–9.6 Szeverenyi I, Cassidy AJ, Chung CW et al. The human intermedi-ate filament database: comprehensive information on a gene fam-ily involved in many human diseases. Hum Mutat 2008; 29:351–60.7 Arin MJ, Oji V, Emmert S et al. Expanding the keratin mutationdatabase: novel and recurrent mutations and genotype–phenotypecorrelations in 28 patients with epidermolytic ichthyosis. Br J Der-matol 2011; 164:442–7.8 Vahlquist A, Ganemo A, Virtanen M. Congenital ichthyosis: anoverview of current and emerging therapies. Acta Derm Venereol2008; 88:4–14.9 Sakakura M, Nishii K, Usui E et al. Bilateral osteonecrosis of thehead of the femur during treatment with retinoic acid in a youngpatient with acute promyelocytic leukemia. Int J Hematol 2006;83:252–3.10 Ellis CN, Pennes DR, Hermann RC et al. Long-term radiographicfollow-up after isotretinoin therapy. J Am Acad Dermatol 1988; 18:1252–61.Funding sources: The Centre for Dermatology and Genetic Medicine atthe University of Dundee is supported by a Wellcome Trust StrategicAward (098439/Z/12/Z to W.H.I.M.).Conflicts of interest: None declared.Short- to intermediate-term follow-up inpatients treated with the combination of311-nm ultraviolet B phototherapy andbiological agentsDOI: 10.1111/bjd.12992DEAR EDITOR, Previous studies1–4 have indicated that ultraviolet(UV) B phototherapy may increase the therapeutic response tobiologics (see also citations in refs 1–4). Most recently, Cal-zavara-Pinton et al. reported that combined treatment with311-nm UVB and etanercept had a synergistic effect for clear-ing chronic plaque-type psoriasis that was previously un-responsive to either form of monotherapy alone.5 However,UVB phototherapy is potentially carcinogenic (although thishas not yet been shown for 311-nm UVB in humans), andthere are safety concerns, particularly in combination withbiological agents.4 We therefore analysed all available follow-up data to detect nonmelanoma skin cancer (NMSC) or mela-noma in patients with psoriasis treated with 311-nm UVBphototherapy in combination with various biologics in differ-ent trials at our institution.1–4From 29 patients with chronic plaque psoriasis who hadbeen treated by combining 311-nm UVB with at least onebiological agent at our department,1–4 28 (10 women, 18men) were included in the follow-up analysis. One patientwas excluded from the risk analysis because of a history of mul-tiple grenz (Bucky) X-ray irradiation-related basal cell carcino-mas before the start of combination treatment, but wasincluded in the statistical analysis of therapeutic efficacyshown in Table 1. One patient, who was discontinued fromthe half-body comparison study with ustekinumab4 because ofa circumscribed herpetic eruption on the thigh on the UV-exposed body half, was excluded from the statistical analysisTable 1 Results on the efficacy of 311-nm ultraviolet (UV) B plus biologic combination therapyBiologic, ref./NCT no.Numberof patientstreated ina studyPercentage PASI reductionWeek 6 Week 12UV No UV UV No UVEtanercept3 5 850 552 907 810Adalimumab2, NCT00638469 6 835 461 677 512GolimumabNCT01088698 2 829 693 n.a. n.a.Ustekinumab4 9 816 541 846 789Alefacept1 14 726 315 827 637All biological agents 36a 811 512* 814 687†Data are mean values calculated from the results of 311-nm UVB half-side comparison studies, previously reported in refs 1–4 and two regis-tered clinical trials. PASI, Psoriasis Area and Severity Index; n.a., not available. aCertain patients participated in more than one trial; thereforethe total number for treatment with biological agents is higher than the total patient number (i.e. 28). *P = 0003; †P = 00255 by two-tailed paired Student’s t-test comparing the UV-irradiated body halves vs. the nonirradiated body halves, based on intention to treat as in thefirst 6 weeks. Note that a portion of the patients (n = 6) were also treated between weeks 7 and 12 with total-body 311-nm UVB (includingthe previously nonirradiated body half).© 2014 British Association of Dermatologists British Journal of Dermatology (2014) 171, pp903–920Correspondence 915

English

                                                                    University of DundeeAvascular necrosis of the hip and diffuse idiopathic skeletal hyperostosis during long-term isotretinoin treatment of epidermolytic ichthyosis due to a novel deletionmutation in KRT10Lamb, R. C.; Lang, J.; Terron-Kwiatowski, A.; Baty, D.; McLean, W. H. I.; Zamiri, M.Published in:British Journal of DermatologyDOI:10.1111/bjd.13049Publication date:2014Licence:CC BYDocument VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Lamb, R. C., Lang, J., Terron-Kwiatowski, A., Baty, D., McLean, W. H. I., & Zamiri, M. (2014). Avascularnecrosis of the hip and diffuse idiopathic skeletal hyperostosis during long-term isotretinoin treatment ofepidermolytic ichthyosis due to a novel deletion mutation in KRT10. British Journal of Dermatology, 171(4), 913-915. https://doi.org/10.1111/bjd.13049General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 30. Oct. 20256 Ghoshal UC, Ghoshal U, Jain M et al. Strongyloides stercoralis infesta-tion associated with septicemia due to intestinal transmural migra-tion of bacteria. J Gastroenterol Hepatol 2002; 17:1331–3.7 Newberry AM, Williams DN, Stauffer WN et al. Strongyloides hyper-infection presenting as acute respiratory failure and gram-negativesepsis. Chest 2005; 128:3681–4.8 Buonfrate D, Requena-Mendez A, Angheben A et al. Severe stron-gyloidiasis: a systematic review of case reports. BMC Infect Dis2013; 13:78.9 Corsini AC. Strongyloidiasis and chronic urticaria. Postgrad Med J1982; 58:247–8.10 Asato R. [Result report of the project for control of the endemicinfection (Strongyloides Stercoralis) in Okinawa prefecture (1987–1992)]. Infect Agents Surveillance Rep 1993; 14:158 (in Japanese).Funding sources: none.Conflicts of interest: none declared.Avascular necrosis of the hip and diffuseidiopathic skeletal hyperostosis during long-term isotretinoin treatment of epidermolyticichthyosis due to a novel deletion mutation inKRT10DOI: 10.1111/bjd.13049DEAR EDITOR, Epidermolytic ichthyosis (EI; OMIM 113800),previously termed bullous congenital ichthyosiform erythro-derma or epidermolytic hyperkeratosis, is a clinically heteroge-neous disorder of keratinization. It is usually characterized bysevere neonatal erythroderma, blistering and fragile skin, withthe subsequent development of hyperkeratosis, predominantlyin flexural areas. It is caused by mutations in either the KRT1or KRT10 genes encoding the suprabasal keratins K1 and K10,respectively.1 Mutations are usually missense substitutions inthe highly conserved alpha-helical rod domains of these kera-tins, which play a critical role in filament formation.2 Wereport a multigeneration kindred with EI due to a novel muta-tion in KRT10.The proband was a 32-year-old woman from Shetland.She presented with widespread fine scale and erythema ofher trunk and limbs, with a history of scaling and rednesssince birth but no blistering, erosions or collodion mem-brane reported. Clinical examination revealed widespread ich-thyosis and erythema affecting the trunk and all four limbs,with more significant hyperkeratosis at the elbows, kneesand ankles but relative sparing of palmoplantar skin (Fig. 1).Her father, uncle and grandmother were affected, and fourfurther generations were reported to be affected. She hadbeen maintained on oral isotretinoin 20–40 mg daily, thusmodifying the clinical appearance, from the age of 13 years,but had recently developed lower back and hip pain. Radio-graphs of the lumbar spine and left hip demonstrated bridg-ing osteophytes form T11 to L1, suggestive of diffuseidiopathic skeletal hyperostosis (DISH), and magnetic reso-nance imaging confirmed the presence of avascular necrosisof the left hip. This was successfully treated with coredecompression of the left hip with improvement in thepatient’s pain.A biopsy of affected skin of the upper limb was obtainedfrom the proband and processed for light microscopy by stan-dard methods. Structural analysis demonstrated acanthosis,marked overlying hyperkeratosis and vacuolar change of theupper epidermal cells with prominent clumping of keratohya-line granules.Following informed consent, genomic DNA samples wereobtained from blood samples from the proband and herfather. Mutation analysis of the coding regions and splice sitesof the KRT1 and KRT10 genes was performed by standard poly-merase chain reaction (PCR) and Sanger sequencing methodsusing specific primers. Sequence analysis of KRT10 revealed apreviously unreported heterozygous deletion of 167 base pairsextending from intron 5 into exon 6 (c.1156–79_1243del),abolishing the intron 5 acceptor splice site (Fig. 2). Thismutation was also present in the proband’s affected father.(a)(b)(c)Fig 1. Family with epidermolytic ichthyosis. (a) Clinical picture ofthe proband: hyperkeratosis of nonplantar sites modified by oralretinoid therapy; (b, c) photographs of her father.Correspondence 913© 2014 The Authors. British Journal of Dermatologypublished by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.This is an open access article under the terms of the Creative Commons Attribution License, which permits use,distribution and reproduction in any medium, provided the original work is properly cited.British Journal of Dermatology (2014) 171, pp903–920RNA was obtained from the proband’s skin biopsy. Follow-ing reverse transcription by standard methods, reverse-trans-criptase PCR was performed using primers flanking thedeletion on exons 5 and 6 of KRT10. RNA analysis demon-strated that the KRT10 c.1156–79_1243del deletion activates acryptic splice site 96 base pairs downstream from the consen-sus intron 5–exon 6 splice site, resulting in an in-frame dele-tion of 32 amino acids, p.Lys386_Gln417, in the K10 protein.This truncated K10 protein, lacking the conserved helix termi-nation motif, is likely to exert a dominant–negative effect onK1/K10 filament formation.The keratin intermediate filament network is the mainstress-bearing structure within the cytoplasm of epithelialcells. EI is caused by mutations in the keratin genes KRT1 andKRT10, which confer structural integrity to suprabasal kerati-nocytes, with most reported mutations being heterozygousmissense mutations.3 Approximately half of all cases of EIoccur sporadically due to a spontaneous mutation.2 In inher-ited cases of EI, it is inherited mostly in a dominant mode,as in this pedigree, although recessive inheritance has beenreported.4 Severe EI has been associated with mutations inthe highly conserved helix boundary motifs, the helix initia-tion and termination peptides and the nonhelical H1 domainof K1 and K10.3 Mutations in the L1–2 linker of K1 or out-side the helix boundary motifs, similar to those seen in mildepidermolysis bullosa simplex, have been described.5 A smallnumber of insertion/deletion mutations and splice-site defectsleading to larger in-frame deletions or rare dinucleotide alter-ations in KRT10, leading to substitution of two adjacentamino acids, have been described.6 Genotype–phenotype cor-relations in EI are very complex, and it is suggested that boththe position of the mutation within K1 or K10 and the nat-ure of the amino acid substitution specifically influence thephenotypic expression of the disease.7 Systemic retinoidsshould be used with caution in EI due to a risk of increasedfragility and a tendency to blistering, although both topicaland oral retinoids are thought to be more effective in thosepatients with EI with K10 mutations compared with K1. It ispostulated that this may be due to the ability of patients withK10 mutations to tolerate better the downregulation of K2caused by retinoids.8To our knowledge, avascular necrosis of the femoral headhas not previously been reported secondary to isotretinoin,and it is unclear whether this contributed to the findings inthe proband. Avascular necrosis of the femoral head occursdue to interruption of the microcirculation of the femoralhead resulting in ischaemia, and may occur spontaneously orin relation to treatment with glucocorticoids, hypertension,sickle cell disease, trauma or other causes. Avascular necrosisof the hip has been reported with retinoids (all-trans-retinoicacid) used to treat haematological conditions; however,affected cases have often received concomitant glucocortic-oids.9 The long-term effects of oral retinoids remain underdebate; however, experience of exposure to isotretinoin at thisdose and for this length of time has been reported in the liter-ature only rarely in comparison with other retinoids.10 Previ-ously reported skeletal abnormalities with retinoid therapyinclude periosteal thickening, premature epiphyseal closure inchildren, osteoporosis, extraspinal tendon and ligament calcifi-cation, osteophytes and bony bridges between vertebrae as inthe proband, in addition to DISH characterized by anteriorspinal ligament calcification. However, there are few prospec-tive studies on the skeletal effects of long-term systemic reti-noids, and many of the bony changes reported are alsoprevalent in the general population. This finding adds to theevidence that KRT10 mutations are the principal cause of auto-somal dominant EI with palmoplantar sparing. It also high-lights the possible side-effects of long-term oral retinoidtreatment in these inherited conditions.AcknowledgmentsWe would like to thank the patients, their family membersand control subjects for their cooperation in this study.R .C . LAMB1J . LANG2A . TERRON-KWIATOWSK I 3D. BATY3W.H. I . MCLEAN4M. ZAM I R I 1 , 51Department of Dermatology, and2Department of Pathology, UniversityHospital Crosshouse, Kilmarnock, U.K.3East of Scotland Genetics Service, NinewellsHospital, Dundee, U.K.4Centre for Dermatology and GeneticMedicine, Division of Molecular Medicine,University of Dundee, Dundee, U.K.5Alan Lyell Centre for Dermatology,Glasgow, U.K.E-mail: rlamb@nhs.netFig 2. DNA sequencing of the KRT10 gene in the proband. Sequencing reveals a novel heterozygous deletion extending from intron 5 into exon 6(K10 c.1156–79_1243del), abolishing the exon 6 acceptor splice site resulting in a shorter aberrant keratin 10 (K10) protein lacking a sequencemotif critically important for keratin filament assembly. The mutation was present in the proband’s affected father but not in unaffected controlsamples.914 Correspondence© 2014 The Authors. British Journal of Dermatologypublished by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.British Journal of Dermatology (2014) 171, pp903–920References1 Oji V, Tadini G, Akiyama M et al. Revised nomenclature and classi-fication of inherited ichthyoses: results of the First Ichthyosis Con-sensus Conference in Soreze 2009. J Am Acad Dermatol 2010;63:607–41.2 Irvine AD, McLean WHI. Human keratin diseases: the increasingspectrum of disease and subtlety of the phenotype–genotype cor-relation. Br J Dermatol 1999; 140:815–28.3 Lane EB, McLean WHI. Keratins and skin disorders. J Pathol 2004;204:355–66.4 Covaciu C, Castori M, De Luca N et al. Lethal autosomal recessiveepidermolytic ichthyosis due to a novel donor splice site mutationin KRT10. Br J Dermatol 2010; 162:1384–7.5 Bolling MC, Bladergroen RS, van Steensal MA et al. A novel muta-tion in the L12 domain of keratin 1 is associated with mild epi-dermolytic ichthyosis. Br J Dermatol 2010; 162:875–9.6 Szeverenyi I, Cassidy AJ, Chung CW et al. The human intermedi-ate filament database: comprehensive information on a gene fam-ily involved in many human diseases. Hum Mutat 2008; 29:351–60.7 Arin MJ, Oji V, Emmert S et al. Expanding the keratin mutationdatabase: novel and recurrent mutations and genotype–phenotypecorrelations in 28 patients with epidermolytic ichthyosis. Br J Der-matol 2011; 164:442–7.8 Vahlquist A, Ganemo A, Virtanen M. Congenital ichthyosis: anoverview of current and emerging therapies. Acta Derm Venereol2008; 88:4–14.9 Sakakura M, Nishii K, Usui E et al. Bilateral osteonecrosis of thehead of the femur during treatment with retinoic acid in a youngpatient with acute promyelocytic leukemia. Int J Hematol 2006;83:252–3.10 Ellis CN, Pennes DR, Hermann RC et al. Long-term radiographicfollow-up after isotretinoin therapy. J Am Acad Dermatol 1988; 18:1252–61.Funding sources: The Centre for Dermatology and Genetic Medicine atthe University of Dundee is supported by a Wellcome Trust StrategicAward (098439/Z/12/Z to W.H.I.M.).Conflicts of interest: None declared.Short- to intermediate-term follow-up inpatients treated with the combination of311-nm ultraviolet B phototherapy andbiological agentsDOI: 10.1111/bjd.12992DEAR EDITOR, Previous studies1–4 have indicated that ultraviolet(UV) B phototherapy may increase the therapeutic response tobiologics (see also citations in refs 1–4). Most recently, Cal-zavara-Pinton et al. reported that combined treatment with311-nm UVB and etanercept had a synergistic effect for clear-ing chronic plaque-type psoriasis that was previously un-responsive to either form of monotherapy alone.5 However,UVB phototherapy is potentially carcinogenic (although thishas not yet been shown for 311-nm UVB in humans), andthere are safety concerns, particularly in combination withbiological agents.4 We therefore analysed all available follow-up data to detect nonmelanoma skin cancer (NMSC) or mela-noma in patients with psoriasis treated with 311-nm UVBphototherapy in combination with various biologics in differ-ent trials at our institution.1–4From 29 patients with chronic plaque psoriasis who hadbeen treated by combining 311-nm UVB with at least onebiological agent at our department,1–4 28 (10 women, 18men) were included in the follow-up analysis. One patientwas excluded from the risk analysis because of a history of mul-tiple grenz (Bucky) X-ray irradiation-related basal cell carcino-mas before the start of combination treatment, but wasincluded in the statistical analysis of therapeutic efficacyshown in Table 1. One patient, who was discontinued fromthe half-body comparison study with ustekinumab4 because ofa circumscribed herpetic eruption on the thigh on the UV-exposed body half, was excluded from the statistical analysisTable 1 Results on the efficacy of 311-nm ultraviolet (UV) B plus biologic combination therapyBiologic, ref./NCT no.Numberof patientstreated ina studyPercentage PASI reductionWeek 6 Week 12UV No UV UV No UVEtanercept3 5 850 552 907 810Adalimumab2, NCT00638469 6 835 461 677 512GolimumabNCT01088698 2 829 693 n.a. n.a.Ustekinumab4 9 816 541 846 789Alefacept1 14 726 315 827 637All biological agents 36a 811 512* 814 687†Data are mean values calculated from the results of 311-nm UVB half-side comparison studies, previously reported in refs 1–4 and two regis-tered clinical trials. PASI, Psoriasis Area and Severity Index; n.a., not available. aCertain patients participated in more than one trial; thereforethe total number for treatment with biological agents is higher than the total patient number (i.e. 28). *P = 0003; †P = 00255 by two-tailed paired Student’s t-test comparing the UV-irradiated body halves vs. the nonirradiated body halves, based on intention to treat as in thefirst 6 weeks. Note that a portion of the patients (n = 6) were also treated between weeks 7 and 12 with total-body 311-nm UVB (includingthe previously nonirradiated body half).© 2014 British Association of Dermatologists British Journal of Dermatology (2014) 171, pp903–920Correspondence 915

Avascular necrosis of the hip and diffuse idiopathic skeletal hyperostosis during long-term isotretinoin treatment of epidermolytic ichthyosis due to a novel deletion mutation in KRT10

Abstract

Similar works

Full text

Available Versions

Crossref

Discovery Research Portal

Discovery Research Portal

Discovery Research Portal