Am J Dermatopathol Volume 36, Number 7, July 2014 5. Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol. 2002;46:477–490. 6. Carillo-Correa M, Vega-Memije E, ToussaintCaire S, et al. Epithelioid leiomyosarcoma: case report and review of the literature. Int J Dermatol. 2005;44:1035–1038.
Three Mutations of CYLD Gene in Chinese Families With Multiple Familial Trichoepithelioma To the Editor: Multiple familial trichoepithelioma (MFT, OMIM 601606) is an autosomal
dominantly inherited disease characterized by numerous skin-colored papules with pilar differentiation. Mutations in the CYLD gene on chromosome 16q12q13 have been identified as the cause of MFT, familial cylindromatosis, and Brooke–Spiegler syndrome (BSS).1 Herein, we performed mutation detection of the CYLD gene in 3 Chinese families with MFT. We found a novel frameshift mutation (c.2255delT) and 2 recurrent nonsense mutations (c.1112C.A and c.2299A.T), the latter was first reported associated with MFT. After informed consent, skin biopsies from the index case from family F1 to F3 were collected. Pedigree analysis in these families was consistent with autosomal-dominant inheritance of the disease (Figs. 1A–C). All the probands presented with a relatively mild
Letters to the Editor
phenotype: mainly, numerous confluent skin-colored papules and nodules, which measured 2–4 mm in diameter, located primarily over central face, and most prominently along the nasolabial folds and the nose. The scalps of the probands were clear (Figs. 1D–F, Table 1). Histological analysis of tumors revealed typical characteristics of trichoepithelioma: islands of basaloid cells with palisading periphery and small horn cysts (Figs. 1G–I). Blood samples were collected from all available individuals and 100 unrelated population-matched controls. Polymerase chain reaction and sequence analysis were performed as described previously.2 Sequence analysis revealed a frameshift mutation in family 1 and family 2 nonsense mutations in family 2 and family 3 (Fig. 2). In family 1, the
FIGURE 1. Three families of the MFT. The pedigree of family 1 (A), family 2 (B), and family 3 (C). Arrows indicates the probands. Clinical features (D, E, and F). Multiple facial skin-colored papules and nodules located on the face of the probands. Histological features (G, H, and I): islands of basaloid cells with palisading periphery and small horn cysts. Supported by grants from the Board of Health Jiading District, Shanghai, China (NO.KYXM 2009-12-6). The authors declare no conflict of interest.
2013 Lippincott Williams & Wilkins
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Am J Dermatopathol Volume 36, Number 7, July 2014
Letters to the Editor
TABLE 1. Clinical Features and CYLD Mutations in 3 MFT Families
Family F1 F2 F3
Clinical Features (the Probands)
Affected No., F/M
Age/Sex
Onset Age, yr
Body Site
2/1 3/3 4/0
24 yr/F 25 yr/F 31 yr/F
20 13 25
Forehead, nose Eyelid, forehead, nose Nose, eyelid
novel frameshift mutation c.2255delT (Leu751fsX774) was detected in exon 17 of the CYLD gene. The mutation changed the reading frame after codon 751, resulting in a premature stop signal at codon 774. The gene with the frameshift mutation would make the truncated protein, which lost the Cys-X-X-Cys pairs [between amino acid (aa) 788 and 856] and the catalytic domain of ubiquitin carboxyl-terminal hydrolases type 2
Nucleotide Change 2255delT 1112C.A 2299A.T
(UCH2-2, aa 871–889). In family 2, the nonsense mutation c.1112C.A (p. S371X) was detected in exon 9, generating a premature stop signal at coding 371 before a cytoskeleton-associated protein– glycine conserved (CAP-Gly, aa 472– 540), proline-rich repeat (aa 388–413 and 446–471), Cys-X-X-Cys pairs, and UCH2 (aa 593–610 and 871–889). In family 3, DNA sequencing revealed an A-to-T transition in exon 17
FIGURE 2. Sequencing of cylindromatosis (CYLD) gene in the pedigree. Frameshift mutation c.2255delT (Leu751fsX774) in exon 17 (A), nonsense mutation 1112C.A (S371X) in exon 9 (B), and nonsense mutation 2299A . T (K767X) in exon 17 (C).
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Amino Acid Change
Exon
Mutation Type
Leu751fsX774 S371X K767X
17 9 17
Frameshift Nonsense Nonsense
(c.2299A.T), generating a premature stop signal at coding 767 before Cys-XX-Cys pairs and the UCH2-2 domain. The mutations were found in all patients but not in the healthy members of each family and 100 unrelated controls expect family 2. In family 2, individual 23 (Fig. 1B) was a carrier of the mutation (c.1112C.A); he has not yet shown any lesion at the age of 9. Thus, we successfully made a genetic diagnosis. The results of clinical features and CYLD mutations in 3 MFT families are summarized in Table 1. To date, a total of 87 distinct germline CYLD mutations have been reported with diverse ethnic and racial background. Of these mutations, 35% (30) are nonsense/missense, 53% (46) are frameshift, 10% (9) are putative splice site, 1% (1) small indel, and 1% (1) gross deletion.3–5 CYLD mutations have been solely identified in the C-terminal in two-thirds of the gene (exons 9–20), even though exons 4–8 are translated. Totally, 6 missense mutations were reported to occur only within the ubiquitin-specific protease (USP) domain of the CYLD protein, and all of them were associated with MFT.2,6–10 In agreement with all previously identified sequence changes in CYLD, the localization of the abnormalities described in this study was in exons 9–20. In family 1, the deletion [c.2255delT (Leu751fsX774)] was in exon 17 in the 39 UTR of CYLD if the deletion will lead to a stable messenger RNA, the mutant RNA will encode a protein, which is part of the USP domain (aa 583–956). The USP domain located in C-terminal region is responsible for deubiquitination activity, and the mutant CYLD protein will lack a part of its functional domain; this explains the clinical phenotype of the patient. Addition with our reported mutation in family 2, the c.1112C.A/p.S371X nonsense mutation was the most 2013 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 7, July 2014
common mutation previously reported associated with BSS, FC, or MFT. The c.2299A.T mutation was also reported previously associated with BSS, but it was first reported associated with MTF in this study. In summary, we found a novel frameshift mutation and 2 recurrent CYLD nonsense mutations associated with MFT. Summarized the reported CYLD mutations, the ongoing recognition of mutations and signaling pathway will insight into the unknown mechanism leading to MFT. Hongli. Lv Cheng Li Yan Li Jinhui. Tang Zheng Zhang† *Department of Dermatology, Jiading Center Hospital, Shanghai, China †Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
2013 Lippincott Williams & Wilkins
ACKNOWLEDGMENTS The authors thank the individuals and their families who participated in this project. REFERENCES 1. Zhang XJ, Liang YH, He PP, et al. Identification of the cylindromatosis tumor-suppressor gene responsible for multiple familial trichoepithelioma. J Invest Dermatol. 2004;122:658–664. 2. Lv HL, Huang YJ, Zhou D, et al. A novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma. J Dermatol Sci. 2008;50:143–146. 3. Grossmann P, Vanecek T, Steiner P, et al. Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens. Am J Dermatopathol. 2013;35:34–44. 4. Kazakov DV, Vanecek T, Zelger B, et al. Multiple (familial) trichoepitheliomas: a clinicopathological and molecular biological study, including CYLD and PTCH gene analysis, of a series of 16 patients. Am J Dermatopathol. 2011;33:251–265.
Letters to the Editor 5. Linos K, Schwartz J, Kazakov DV, et al. Recurrent CYLD nonsense mutation associated with a severe, disfiguring phenotype in an African American family with multiple familial trichoepithelioma. Am J Dermatopathol. 2011; 33:640–642. 6. Zuo YG, Xu Y, Wang B, et al. A novel mutation of CYLD in a Chinese family with multiple familial trichoepithelioma and no CYLD protein expression in the tumour tissue. Br J Dermatol. 2007;157:818–821. 7. Almeida S, Maillard C, Itin P, et al. Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity. J Invest Dermatol. 2008;128:587–593. 8. Wang FX, Yang LJ, Li M, et al. A novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma. Arch Dermatol Res. 2010;302:67–70. 9. Espana A, Garcia-Amigot F, Aguado L, et al. A novel missense mutation in the CYLD gene in a Spanish family with multiple familial trichoepithelioma. Arch Dermatol. 2007;143: 1209–1210. 10. Zheng G, Hu L, Huang W, et al. CYLD mutation causes multiple familial trichoepithelioma in three Chinese families. Hum Mutat. 2004; 23:400.
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Three Mutations of CYLD Gene in Chinese Families With Multiple Familial Trichoepithelioma To the Editor: Multiple familial trichoepithelioma (MFT, OMIM 601606) is an autosomal
dominantly inherited disease characterized by numerous skin-colored papules with pilar differentiation. Mutations in the CYLD gene on chromosome 16q12q13 have been identified as the cause of MFT, familial cylindromatosis, and Brooke–Spiegler syndrome (BSS).1 Herein, we performed mutation detection of the CYLD gene in 3 Chinese families with MFT. We found a novel frameshift mutation (c.2255delT) and 2 recurrent nonsense mutations (c.1112C.A and c.2299A.T), the latter was first reported associated with MFT. After informed consent, skin biopsies from the index case from family F1 to F3 were collected. Pedigree analysis in these families was consistent with autosomal-dominant inheritance of the disease (Figs. 1A–C). All the probands presented with a relatively mild
Letters to the Editor
phenotype: mainly, numerous confluent skin-colored papules and nodules, which measured 2–4 mm in diameter, located primarily over central face, and most prominently along the nasolabial folds and the nose. The scalps of the probands were clear (Figs. 1D–F, Table 1). Histological analysis of tumors revealed typical characteristics of trichoepithelioma: islands of basaloid cells with palisading periphery and small horn cysts (Figs. 1G–I). Blood samples were collected from all available individuals and 100 unrelated population-matched controls. Polymerase chain reaction and sequence analysis were performed as described previously.2 Sequence analysis revealed a frameshift mutation in family 1 and family 2 nonsense mutations in family 2 and family 3 (Fig. 2). In family 1, the
FIGURE 1. Three families of the MFT. The pedigree of family 1 (A), family 2 (B), and family 3 (C). Arrows indicates the probands. Clinical features (D, E, and F). Multiple facial skin-colored papules and nodules located on the face of the probands. Histological features (G, H, and I): islands of basaloid cells with palisading periphery and small horn cysts. Supported by grants from the Board of Health Jiading District, Shanghai, China (NO.KYXM 2009-12-6). The authors declare no conflict of interest.
2013 Lippincott Williams & Wilkins
www.amjdermatopathology.com |
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Am J Dermatopathol Volume 36, Number 7, July 2014
Letters to the Editor
TABLE 1. Clinical Features and CYLD Mutations in 3 MFT Families
Family F1 F2 F3
Clinical Features (the Probands)
Affected No., F/M
Age/Sex
Onset Age, yr
Body Site
2/1 3/3 4/0
24 yr/F 25 yr/F 31 yr/F
20 13 25
Forehead, nose Eyelid, forehead, nose Nose, eyelid
novel frameshift mutation c.2255delT (Leu751fsX774) was detected in exon 17 of the CYLD gene. The mutation changed the reading frame after codon 751, resulting in a premature stop signal at codon 774. The gene with the frameshift mutation would make the truncated protein, which lost the Cys-X-X-Cys pairs [between amino acid (aa) 788 and 856] and the catalytic domain of ubiquitin carboxyl-terminal hydrolases type 2
Nucleotide Change 2255delT 1112C.A 2299A.T
(UCH2-2, aa 871–889). In family 2, the nonsense mutation c.1112C.A (p. S371X) was detected in exon 9, generating a premature stop signal at coding 371 before a cytoskeleton-associated protein– glycine conserved (CAP-Gly, aa 472– 540), proline-rich repeat (aa 388–413 and 446–471), Cys-X-X-Cys pairs, and UCH2 (aa 593–610 and 871–889). In family 3, DNA sequencing revealed an A-to-T transition in exon 17
FIGURE 2. Sequencing of cylindromatosis (CYLD) gene in the pedigree. Frameshift mutation c.2255delT (Leu751fsX774) in exon 17 (A), nonsense mutation 1112C.A (S371X) in exon 9 (B), and nonsense mutation 2299A . T (K767X) in exon 17 (C).
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| www.amjdermatopathology.com
Amino Acid Change
Exon
Mutation Type
Leu751fsX774 S371X K767X
17 9 17
Frameshift Nonsense Nonsense
(c.2299A.T), generating a premature stop signal at coding 767 before Cys-XX-Cys pairs and the UCH2-2 domain. The mutations were found in all patients but not in the healthy members of each family and 100 unrelated controls expect family 2. In family 2, individual 23 (Fig. 1B) was a carrier of the mutation (c.1112C.A); he has not yet shown any lesion at the age of 9. Thus, we successfully made a genetic diagnosis. The results of clinical features and CYLD mutations in 3 MFT families are summarized in Table 1. To date, a total of 87 distinct germline CYLD mutations have been reported with diverse ethnic and racial background. Of these mutations, 35% (30) are nonsense/missense, 53% (46) are frameshift, 10% (9) are putative splice site, 1% (1) small indel, and 1% (1) gross deletion.3–5 CYLD mutations have been solely identified in the C-terminal in two-thirds of the gene (exons 9–20), even though exons 4–8 are translated. Totally, 6 missense mutations were reported to occur only within the ubiquitin-specific protease (USP) domain of the CYLD protein, and all of them were associated with MFT.2,6–10 In agreement with all previously identified sequence changes in CYLD, the localization of the abnormalities described in this study was in exons 9–20. In family 1, the deletion [c.2255delT (Leu751fsX774)] was in exon 17 in the 39 UTR of CYLD if the deletion will lead to a stable messenger RNA, the mutant RNA will encode a protein, which is part of the USP domain (aa 583–956). The USP domain located in C-terminal region is responsible for deubiquitination activity, and the mutant CYLD protein will lack a part of its functional domain; this explains the clinical phenotype of the patient. Addition with our reported mutation in family 2, the c.1112C.A/p.S371X nonsense mutation was the most 2013 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 7, July 2014
common mutation previously reported associated with BSS, FC, or MFT. The c.2299A.T mutation was also reported previously associated with BSS, but it was first reported associated with MTF in this study. In summary, we found a novel frameshift mutation and 2 recurrent CYLD nonsense mutations associated with MFT. Summarized the reported CYLD mutations, the ongoing recognition of mutations and signaling pathway will insight into the unknown mechanism leading to MFT. Hongli. Lv Cheng Li Yan Li Jinhui. Tang Zheng Zhang† *Department of Dermatology, Jiading Center Hospital, Shanghai, China †Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
2013 Lippincott Williams & Wilkins
ACKNOWLEDGMENTS The authors thank the individuals and their families who participated in this project. REFERENCES 1. Zhang XJ, Liang YH, He PP, et al. Identification of the cylindromatosis tumor-suppressor gene responsible for multiple familial trichoepithelioma. J Invest Dermatol. 2004;122:658–664. 2. Lv HL, Huang YJ, Zhou D, et al. A novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma. J Dermatol Sci. 2008;50:143–146. 3. Grossmann P, Vanecek T, Steiner P, et al. Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens. Am J Dermatopathol. 2013;35:34–44. 4. Kazakov DV, Vanecek T, Zelger B, et al. Multiple (familial) trichoepitheliomas: a clinicopathological and molecular biological study, including CYLD and PTCH gene analysis, of a series of 16 patients. Am J Dermatopathol. 2011;33:251–265.
Letters to the Editor 5. Linos K, Schwartz J, Kazakov DV, et al. Recurrent CYLD nonsense mutation associated with a severe, disfiguring phenotype in an African American family with multiple familial trichoepithelioma. Am J Dermatopathol. 2011; 33:640–642. 6. Zuo YG, Xu Y, Wang B, et al. A novel mutation of CYLD in a Chinese family with multiple familial trichoepithelioma and no CYLD protein expression in the tumour tissue. Br J Dermatol. 2007;157:818–821. 7. Almeida S, Maillard C, Itin P, et al. Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity. J Invest Dermatol. 2008;128:587–593. 8. Wang FX, Yang LJ, Li M, et al. A novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma. Arch Dermatol Res. 2010;302:67–70. 9. Espana A, Garcia-Amigot F, Aguado L, et al. A novel missense mutation in the CYLD gene in a Spanish family with multiple familial trichoepithelioma. Arch Dermatol. 2007;143: 1209–1210. 10. Zheng G, Hu L, Huang W, et al. CYLD mutation causes multiple familial trichoepithelioma in three Chinese families. Hum Mutat. 2004; 23:400.
www.amjdermatopathology.com |
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