These articles have been accepted for publication in the British Journal of Dermatology and are currently being edited and typeset. Readers should note that articles published below have been fully refereed, but have not been through the copy-editing and proof correction process. WileyBlackwell and the British Association of Dermatologists cannot be held responsible for errors or consequences arising from the use of information contained in these articles; nor do the views and opinions expressed necessarily reflect those of Wiley-Blackwell or the British Association of Dermatologists This article is protected by copyright. All rights reserved. Received Date : 31-Aug-2014 Revised Date : 31-Oct-2014 Accepted Date : 03-Dec-2014 Article type
: Correspondence
Extensive lentigo simplex, linear epidermolytic nevus and epidermolytic nevus comedonicus caused by a somatic mutation in KRT10
L. Samuelov1, O. Sarig1, A. Gat2, S. Halachmi3,4, S. Shalev5,6, E. Sprecher1,7
1
Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel;
2
Department of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel;
3
Rabin Medical Center, Petach Tikva, Israel;
4
Herzelia Dermatology and Laser Center, Herzelia Pituach, Israel;
5
Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel;
6
Institute of Human Genetics, Haemek Medical Center, Afula, Israel;
7
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-
Aviv University, Ramat-Aviv, Israel
This article is protected by copyright. All rights reserved. Correspondence should be addressed to: Dr. Liat Samuelov Department of Dermatology Tel Aviv Sourasky Medical Center 6 Weizman Street, Tel Aviv 64239 Israel Email: [email protected] Tel: 972-3-6974287 Fax: 972-3-6974810
Key words: Epidermolytic hyperkeratosis, epidermal nevus, nevus comedonicus, keratin 10
To the Editor, Epidermolytic epidermal nevus and nevus comedonicus are rare cutaneous conditions1. In the present study, we describe a hitherto unreported association between extensive lentigo simplex, epidermolytic epidermal nevus and epidermolytic nevus comedonicus, caused by a somatic heterozygous mutation in KRT10. A 33-year-old-man of Arab Muslim descent with a personal history of rheumatoid arthritis and a personal and family history of short stature, presented to our department with asymptomatic brown patches and linear skin lesions on the trunk and along the extremities. The skin lesions were already observed at birth but extended gradually during the first years of life and there was no evidence of skin fragility or blister formation on affected skin. He denied any similar findings among his family members Physical examination revealed three morphologically distinct types of lesions: linear brown verrucous plaques located along the right upper extremity and trunk (Fig. 1a); pink verrucous plaques with conspicuous comedones located over the lower back (Fig. 1b); and a large dark brown demarcated patch covering a large part of the right upper abdomen surface (Fig. 1c). On histopathology, the first two lesions demonstrated epidermolytic hyperkeratosis (Fig. 2a-b) while the third lesion showed histopathological findings consistent with lentigo simplex (Fig. 2c).
This article is protected by copyright. All rights reserved. The presence of epidermolytic changes in two lesions with linear configuration raised the possibility that they may be due to somatic mutations in KRT10 or KRT12,3. After having received the patient’s written and informed consent according to a protocol approved by our institutional review board and by the Israel National Committee for Human Genetic Studies, total RNA was extracted from a whole skin punch biopsy obtained from the nevus comedonicus lesion and reverse-transcribed as previously described4. cDNA direct sequencing led to the identification of a heterozygous mutation, p.R156C, in the KRT10 gene encoding keratin 10. No KRT10 mutation was found in DNA extracted from the patient's peripheral blood (Fig. 2d). The mutation was confirmed at the cDNA level using the PCR-RFLP assay (Fig. 2e). Here we report the association of lentigo simplex, linear epidermolytic nevus and nevus comedonicus caused by a somatic mutation in KRT10. This clinical constellation has to the best of our knowledge never been previously reported. Likewise, although the exceedingly rare epidermolytic variant of nevus comedonicus has been previously reported5, it has not yet been shown to be associated with a somatic mutation as in the present study. The association described in the present study is in some aspects reminiscent of previous cases reported under the denomination of phakomatosis pigmentokeratotica (PPK). PPK is a rare epidermal nevus syndrome characterized by the coexistence of a sebaceous nevus and a speckled lentiginous nevus and may be associated with other extracutaneous features (e.g. neurological, skeletal)1,6. The epidermal nevus demonstrates hyperpigmentation of the stratum basale associated with melanocytic nests at the dermoepidermal junction. The occurrence of two different nevus types in a single patient has been explained by the twin spotting phenomenon, where somatic recombination of two nonallelic recessive mutations is predicted to result in two different clones derived from neighboring daughter cells which are homozygous for one recessive mutation. This may result in two distinct nevi in close proximity7. However, more recently, it has been shown that a single heterozygous postzygotic-activating HRAS mutation accounts for the two distinct nevus types seen in PPK, a fact that contradicts the twin spotting theory and actually supports the possibility that two distinct nevoid phenotypes may result from the same somatic defect8. In the present case, although we had no access to material derived from the lentigo simplex, it is of interest to note that recent data have underscores the role of basal keratins in the regulation of skin pigmentation9-13,14. More relevant to the present case, it is of interest to note Dsk12 mice, which are a model for epidermolytic ichthyosis and carry a heterozygous mutation in Krt1, that display marked footpads pigmentation by 2 months of age associated with increased epidermal pigment at the tips of the rete ridges and within the eccrine ducts, in addition to the classical findings of blistering and hyperkeratosis15.
This article is protected by copyright. All rights reserved. In conclusion, we report a unique combination of nevoid lesions including extensive lentigo simplex, linear epidermolytic epidermal nevus and epidermolytic nevus comedonicus, caused by a somatic heterozygous mutation in KRT10.
Acknowledgments We are grateful to our patient for his participation in this study. This study was supported in part by a generous donation of the Ram family.
Conflict of interest The authors do not have any conflict of interest.
Figure legends Figure 1. Clinical manifestations. (a) The lesion located at the right upper extremity and trunk is featuring verrucous papules with linear configuration (b) The lower back lesion is characterized by pink verrucous plaques with comedones (c) Dark brown demarcated patch located at the right upper abdomen. Figure 2. Histopathological and molecular findings. (a-b) The right upper trunk (a) and lower back (b) lesions demonstrate hyperkeratosis with evidence of perinuclear halo, basophilic and clumped keratohyaline granules in the upper spinous and granular layers, compatible with epidermolytc hyperkeratosis. Hematoxylin and eosin (H/E) staining x200 (a) and x100 (b). (c) The dark brown patch located at the right upper abdomen reveals histopathological findings of mild epidermal acanthosis, slightly increased number of uniformly dispersed single melanocytes in the basal layer and basal hyperpigmentation compatible with lentigo simplex. H/E staining x200. (d) cDNA direct sequencing of KRT10 revealed a heterozygous mutation c.C466T, while no mutation was found in direct sequencing of DNA extracted from the patient's peripheral blood (gDNA). (e) A PCR-RFLP assay was used to confirm the c.C466T mutation. Patient and wt cDNAs PCRamplified a 287 bp fragment with forward primer 5’- CTTTGGTGGTG GATTTGGAG -3’ and reverse primer 5’- TGTCGATCTGAA GCAGGATG -3’. The mutation c.C466T abolishes a recognition site for the endonuclease AciI and is associated with the presence of a 278 bp fragment.
This article is protected by copyright. All rights reserved. References 1 2 3 4
5 6 7 8
9 10
11 12
13 14 15
Happle R. The group of epidermal nevus syndromes Part I. Well defined phenotypes. Journal of the American Academy of Dermatology 2010; 63: 1-22; quiz 3-4. Paller AS, Syder AJ, Chan YM et al. Genetic and clinical mosaicism in a type of epidermal nevus. The New England journal of medicine 1994; 331: 1408-15. Tsubota A, Akiyama M, Sakai K et al. Keratin 1 gene mutation detected in epidermal nevus with epidermolytic hyperkeratosis. The Journal of investigative dermatology 2007; 127: 1371-4. Pavlovsky M, Fuchs-Telem D, Nousbeck J et al. Molecular evidence for the role of Xchromosome inactivation in linear presentation of X-linked hypohidrotic ectodermal dysplasia. Clinical and experimental dermatology 2012; 37: 186-8. Su WP. Histopathologic varieties of epidermal nevus. A study of 160 cases. The American Journal of dermatopathology 1982; 4: 161-70. Happle R, Hoffmann R, Restano L et al. Phacomatosis pigmentokeratotica: a melanocyticepidermal twin nevus syndrome. Am J Med Genet 1996; 65: 363-5. Happle R, Koopman R, Mier PD. Hypothesis: vascular twin naevi and somatic recombination in man. Lancet 1990; 335: 376-8. Groesser L, Herschberger E, Sagrera A et al. Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell. J Invest Dermatol 2013; 133: 19982003. Echeverria-Garcia B, Vicente A, Hernandez A et al. Epidermolysis bullosa simplex with mottled pigmentation: a family report and review. Pediatr Dermatol 2013; 30: e125-31. Glasz-Bona A, Medvecz M, Viragh Z et al. Epidermolysis bullosa simplex with mottled pigmentation - mutation analysis proved the diagnosis in a four-generation pedigree. Eur J Dermatol 2010; 20: 698-700. Irvine AD, Rugg EL, Lane EB et al. Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol 2001; 144: 40-5. Uttam J, Hutton E, Coulombe PA et al. The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. Proceedings of the National Academy of Sciences of the United States of America 1996; 93: 9079-84. Harel A, Bergman R, Indelman M et al. Epidermolysis bullosa simplex with mottled pigmentation resulting from a recurrent mutation in KRT14. J Invest Dermatol 2006; 126: 1654-7. Betz RC, Planko L, Eigelshoven S et al. Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet 2006; 78: 510-9. McGowan KA, Aradhya S, Fuchs H et al. A mouse keratin 1 mutation causes dark skin and epidermolytic hyperkeratosis. J Invest Dermatol 2006; 126: 1013-6.
This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
: Correspondence
Extensive lentigo simplex, linear epidermolytic nevus and epidermolytic nevus comedonicus caused by a somatic mutation in KRT10
L. Samuelov1, O. Sarig1, A. Gat2, S. Halachmi3,4, S. Shalev5,6, E. Sprecher1,7
1
Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel;
2
Department of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel;
3
Rabin Medical Center, Petach Tikva, Israel;
4
Herzelia Dermatology and Laser Center, Herzelia Pituach, Israel;
5
Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel;
6
Institute of Human Genetics, Haemek Medical Center, Afula, Israel;
7
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-
Aviv University, Ramat-Aviv, Israel
This article is protected by copyright. All rights reserved. Correspondence should be addressed to: Dr. Liat Samuelov Department of Dermatology Tel Aviv Sourasky Medical Center 6 Weizman Street, Tel Aviv 64239 Israel Email: [email protected] Tel: 972-3-6974287 Fax: 972-3-6974810
Key words: Epidermolytic hyperkeratosis, epidermal nevus, nevus comedonicus, keratin 10
To the Editor, Epidermolytic epidermal nevus and nevus comedonicus are rare cutaneous conditions1. In the present study, we describe a hitherto unreported association between extensive lentigo simplex, epidermolytic epidermal nevus and epidermolytic nevus comedonicus, caused by a somatic heterozygous mutation in KRT10. A 33-year-old-man of Arab Muslim descent with a personal history of rheumatoid arthritis and a personal and family history of short stature, presented to our department with asymptomatic brown patches and linear skin lesions on the trunk and along the extremities. The skin lesions were already observed at birth but extended gradually during the first years of life and there was no evidence of skin fragility or blister formation on affected skin. He denied any similar findings among his family members Physical examination revealed three morphologically distinct types of lesions: linear brown verrucous plaques located along the right upper extremity and trunk (Fig. 1a); pink verrucous plaques with conspicuous comedones located over the lower back (Fig. 1b); and a large dark brown demarcated patch covering a large part of the right upper abdomen surface (Fig. 1c). On histopathology, the first two lesions demonstrated epidermolytic hyperkeratosis (Fig. 2a-b) while the third lesion showed histopathological findings consistent with lentigo simplex (Fig. 2c).
This article is protected by copyright. All rights reserved. The presence of epidermolytic changes in two lesions with linear configuration raised the possibility that they may be due to somatic mutations in KRT10 or KRT12,3. After having received the patient’s written and informed consent according to a protocol approved by our institutional review board and by the Israel National Committee for Human Genetic Studies, total RNA was extracted from a whole skin punch biopsy obtained from the nevus comedonicus lesion and reverse-transcribed as previously described4. cDNA direct sequencing led to the identification of a heterozygous mutation, p.R156C, in the KRT10 gene encoding keratin 10. No KRT10 mutation was found in DNA extracted from the patient's peripheral blood (Fig. 2d). The mutation was confirmed at the cDNA level using the PCR-RFLP assay (Fig. 2e). Here we report the association of lentigo simplex, linear epidermolytic nevus and nevus comedonicus caused by a somatic mutation in KRT10. This clinical constellation has to the best of our knowledge never been previously reported. Likewise, although the exceedingly rare epidermolytic variant of nevus comedonicus has been previously reported5, it has not yet been shown to be associated with a somatic mutation as in the present study. The association described in the present study is in some aspects reminiscent of previous cases reported under the denomination of phakomatosis pigmentokeratotica (PPK). PPK is a rare epidermal nevus syndrome characterized by the coexistence of a sebaceous nevus and a speckled lentiginous nevus and may be associated with other extracutaneous features (e.g. neurological, skeletal)1,6. The epidermal nevus demonstrates hyperpigmentation of the stratum basale associated with melanocytic nests at the dermoepidermal junction. The occurrence of two different nevus types in a single patient has been explained by the twin spotting phenomenon, where somatic recombination of two nonallelic recessive mutations is predicted to result in two different clones derived from neighboring daughter cells which are homozygous for one recessive mutation. This may result in two distinct nevi in close proximity7. However, more recently, it has been shown that a single heterozygous postzygotic-activating HRAS mutation accounts for the two distinct nevus types seen in PPK, a fact that contradicts the twin spotting theory and actually supports the possibility that two distinct nevoid phenotypes may result from the same somatic defect8. In the present case, although we had no access to material derived from the lentigo simplex, it is of interest to note that recent data have underscores the role of basal keratins in the regulation of skin pigmentation9-13,14. More relevant to the present case, it is of interest to note Dsk12 mice, which are a model for epidermolytic ichthyosis and carry a heterozygous mutation in Krt1, that display marked footpads pigmentation by 2 months of age associated with increased epidermal pigment at the tips of the rete ridges and within the eccrine ducts, in addition to the classical findings of blistering and hyperkeratosis15.
This article is protected by copyright. All rights reserved. In conclusion, we report a unique combination of nevoid lesions including extensive lentigo simplex, linear epidermolytic epidermal nevus and epidermolytic nevus comedonicus, caused by a somatic heterozygous mutation in KRT10.
Acknowledgments We are grateful to our patient for his participation in this study. This study was supported in part by a generous donation of the Ram family.
Conflict of interest The authors do not have any conflict of interest.
Figure legends Figure 1. Clinical manifestations. (a) The lesion located at the right upper extremity and trunk is featuring verrucous papules with linear configuration (b) The lower back lesion is characterized by pink verrucous plaques with comedones (c) Dark brown demarcated patch located at the right upper abdomen. Figure 2. Histopathological and molecular findings. (a-b) The right upper trunk (a) and lower back (b) lesions demonstrate hyperkeratosis with evidence of perinuclear halo, basophilic and clumped keratohyaline granules in the upper spinous and granular layers, compatible with epidermolytc hyperkeratosis. Hematoxylin and eosin (H/E) staining x200 (a) and x100 (b). (c) The dark brown patch located at the right upper abdomen reveals histopathological findings of mild epidermal acanthosis, slightly increased number of uniformly dispersed single melanocytes in the basal layer and basal hyperpigmentation compatible with lentigo simplex. H/E staining x200. (d) cDNA direct sequencing of KRT10 revealed a heterozygous mutation c.C466T, while no mutation was found in direct sequencing of DNA extracted from the patient's peripheral blood (gDNA). (e) A PCR-RFLP assay was used to confirm the c.C466T mutation. Patient and wt cDNAs PCRamplified a 287 bp fragment with forward primer 5’- CTTTGGTGGTG GATTTGGAG -3’ and reverse primer 5’- TGTCGATCTGAA GCAGGATG -3’. The mutation c.C466T abolishes a recognition site for the endonuclease AciI and is associated with the presence of a 278 bp fragment.
This article is protected by copyright. All rights reserved. References 1 2 3 4
5 6 7 8
9 10
11 12
13 14 15
Happle R. The group of epidermal nevus syndromes Part I. Well defined phenotypes. Journal of the American Academy of Dermatology 2010; 63: 1-22; quiz 3-4. Paller AS, Syder AJ, Chan YM et al. Genetic and clinical mosaicism in a type of epidermal nevus. The New England journal of medicine 1994; 331: 1408-15. Tsubota A, Akiyama M, Sakai K et al. Keratin 1 gene mutation detected in epidermal nevus with epidermolytic hyperkeratosis. The Journal of investigative dermatology 2007; 127: 1371-4. Pavlovsky M, Fuchs-Telem D, Nousbeck J et al. Molecular evidence for the role of Xchromosome inactivation in linear presentation of X-linked hypohidrotic ectodermal dysplasia. Clinical and experimental dermatology 2012; 37: 186-8. Su WP. Histopathologic varieties of epidermal nevus. A study of 160 cases. The American Journal of dermatopathology 1982; 4: 161-70. Happle R, Hoffmann R, Restano L et al. Phacomatosis pigmentokeratotica: a melanocyticepidermal twin nevus syndrome. Am J Med Genet 1996; 65: 363-5. Happle R, Koopman R, Mier PD. Hypothesis: vascular twin naevi and somatic recombination in man. Lancet 1990; 335: 376-8. Groesser L, Herschberger E, Sagrera A et al. Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell. J Invest Dermatol 2013; 133: 19982003. Echeverria-Garcia B, Vicente A, Hernandez A et al. Epidermolysis bullosa simplex with mottled pigmentation: a family report and review. Pediatr Dermatol 2013; 30: e125-31. Glasz-Bona A, Medvecz M, Viragh Z et al. Epidermolysis bullosa simplex with mottled pigmentation - mutation analysis proved the diagnosis in a four-generation pedigree. Eur J Dermatol 2010; 20: 698-700. Irvine AD, Rugg EL, Lane EB et al. Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol 2001; 144: 40-5. Uttam J, Hutton E, Coulombe PA et al. The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. Proceedings of the National Academy of Sciences of the United States of America 1996; 93: 9079-84. Harel A, Bergman R, Indelman M et al. Epidermolysis bullosa simplex with mottled pigmentation resulting from a recurrent mutation in KRT14. J Invest Dermatol 2006; 126: 1654-7. Betz RC, Planko L, Eigelshoven S et al. Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet 2006; 78: 510-9. McGowan KA, Aradhya S, Fuchs H et al. A mouse keratin 1 mutation causes dark skin and epidermolytic hyperkeratosis. J Invest Dermatol 2006; 126: 1013-6.
This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
