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PLOS Currents Evidence on Genomic Tests. 2015 Feb 19 . Edition 1. doi: )] TJ ET BT 26.250 627.533 Td /F1 9.8 Tf [(10.1371/currents.eogt.45c4e63dd43d62e12228cc5264d6a0db.)] TJ ET q 15.000 60.815 577.500 564.337 re W n 0.271 0.267 0.267 rg BT 26.250 598.430 Td /F6 12.0 Tf [(Abstract)] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(The clinical presentation of multiple, rare, skin appendage tumours called cylindromas has been attributed to germline mutations )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(in the tumour suppressor gene )] TJ ET BT 161.190 566.571 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 187.193 566.571 Td /F1 9.8 Tf [( \(OMIM 605018\). Brooke-Spiegler Syndrome \(BSS\), familial cylindromatosis \(FC\) and )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(multiple familial trichoepitheliomas \(MFT\) \(OMIM #605041, #132700, #601606 respectively\) differ due to the types of other skin )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(appendage tumour seen together with cylindroma, such as spiradenoma and trichoepithelioma. Previously thought to be )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(separate entities, they are now viewed as allelic variants with overlapping phenotypes, supported by mutation analysis of )] TJ ET BT 548.655 530.857 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(. The conditions display autosomal dominant inheritance and affected individuals develop multiple benign skin tumours most )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(commonly on the head and neck.)] TJ ET BT 26.250 487.643 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 52.253 487.643 Td /F1 9.8 Tf [( testing can be performed using PCR and Sanger sequencing for patients with:)] TJ ET BT 26.250 475.738 Td /F1 9.8 Tf [(1. Multiple cylindromas, spiradenomas or trichoepitheliomas.)] TJ ET BT 26.250 463.833 Td /F1 9.8 Tf [(2. A single cylindroma, spiradenoma or trichoepithelioma and an affected first-degree relative with any of these tumours.)] TJ ET BT 26.250 451.929 Td /F1 9.8 Tf [(3. An asymptomatic family member at 50% risk with a known mutation in the family.)] TJ ET BT 26.250 415.326 Td /F6 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 395.372 Td /F1 9.8 Tf [(Neil Rajan is a Wellcome Intermediate Fellow. The funders had no role in study design, data collection and analysis, decision to )] TJ ET BT 26.250 383.467 Td /F1 9.8 Tf [(publish, or preparation of the manuscript.)] TJ ET BT 26.250 354.365 Td /F6 12.0 Tf [(Clinical Phenotype)] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(BSS, FC and MFT arise from heterozygous mutations in the )] TJ ET BT 287.433 334.410 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 313.436 334.410 Td /F1 9.8 Tf [( gene)] TJ ET 0.267 0.267 0.267 rg BT 337.831 335.918 Td /F6 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 342.649 334.410 Td /F1 9.8 Tf [(. Cylindromas are benign appendageal tumours )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(occurring mainly on the scalp, but can occur on any hair bearing skin. The lesions typically present as painless, smooth pink )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(nodules, which may be either solitary or clustered together. They are slow-growing and vary in size from a few millimetres to )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(over six centimetres.)] TJ ET 0.965 0.965 0.965 rg 26.250 60.815 555.000 228.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 288.815 m 581.250 288.815 l 581.250 288.065 l 26.250 288.065 l f q 225.000 0 0 212.250 35.250 66.815 cm /I3 Do Q q 35.250 60.815 537.000 0.000 re W n Q Q q 15.000 684.354 577.500 53.646 re W n 0.271 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(CYLD)] TJ ET 0.267 0.267 0.267 rg BT 69.831 718.042 Td /F3 21.0 Tf [( GeneticTesting for Brooke-Spiegler Syndrome, Familial )] TJ ET BT 15.000 693.094 Td /F3 21.0 Tf [(Cylindromatosis and Multiple Familial Trichoepitheliomas)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F4 9.8 Tf [(February 19, 2015)] TJ ET BT 93.263 675.088 Td /F4 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 98.138 675.088 Td /F4 9.8 Tf [(Diagnostic)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Anna Dubois)] TJ ET 0.271 0.267 0.267 rg BT 82.069 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 87.490 663.247 Td /F1 9.8 Tf [(Valerie Wilson)] TJ ET 0.271 0.267 0.267 rg BT 149.792 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 155.213 663.247 Td /F1 9.8 Tf [(David Bourn)] TJ ET 0.271 0.267 0.267 rg BT 208.858 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 214.279 663.247 Td /F1 9.8 Tf [(Neil Rajan)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Dubois A, Wilson V, Bourn D, Rajan N. )] TJ ET BT 196.934 651.342 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 222.937 651.342 Td /F1 9.8 Tf [( GeneticTesting for Brooke-Spiegler Syndrome, Familial Cylindromatosis and )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Multiple Familial Trichoepitheliomas. PLOS Currents Evidence on Genomic Tests. 2015 Feb 19 . Edition 1. doi: )] TJ ET BT 26.250 627.533 Td /F1 9.8 Tf [(10.1371/currents.eogt.45c4e63dd43d62e12228cc5264d6a0db.)] TJ ET q 15.000 60.815 577.500 564.337 re W n 0.271 0.267 0.267 rg BT 26.250 598.430 Td /F6 12.0 Tf [(Abstract)] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(The clinical presentation of multiple, rare, skin appendage tumours called cylindromas has been attributed to germline mutations )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(in the tumour suppressor gene )] TJ ET BT 161.190 566.571 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 187.193 566.571 Td /F1 9.8 Tf [( \(OMIM 605018\). Brooke-Spiegler Syndrome \(BSS\), familial cylindromatosis \(FC\) and )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(multiple familial trichoepitheliomas \(MFT\) \(OMIM #605041, #132700, #601606 respectively\) differ due to the types of other skin )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(appendage tumour seen together with cylindroma, such as spiradenoma and trichoepithelioma. Previously thought to be )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(separate entities, they are now viewed as allelic variants with overlapping phenotypes, supported by mutation analysis of )] TJ ET BT 548.655 530.857 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(. The conditions display autosomal dominant inheritance and affected individuals develop multiple benign skin tumours most )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(commonly on the head and neck.)] TJ ET BT 26.250 487.643 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 52.253 487.643 Td /F1 9.8 Tf [( testing can be performed using PCR and Sanger sequencing for patients with:)] TJ ET BT 26.250 475.738 Td /F1 9.8 Tf [(1. Multiple cylindromas, spiradenomas or trichoepitheliomas.)] TJ ET BT 26.250 463.833 Td /F1 9.8 Tf [(2. A single cylindroma, spiradenoma or trichoepithelioma and an affected first-degree relative with any of these tumours.)] TJ ET BT 26.250 451.929 Td /F1 9.8 Tf [(3. An asymptomatic family member at 50% risk with a known mutation in the family.)] TJ ET BT 26.250 415.326 Td /F6 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 395.372 Td /F1 9.8 Tf [(Neil Rajan is a Wellcome Intermediate Fellow. The funders had no role in study design, data collection and analysis, decision to )] TJ ET BT 26.250 383.467 Td /F1 9.8 Tf [(publish, or preparation of the manuscript.)] TJ ET BT 26.250 354.365 Td /F6 12.0 Tf [(Clinical Phenotype)] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(BSS, FC and MFT arise from heterozygous mutations in the )] TJ ET BT 287.433 334.410 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 313.436 334.410 Td /F1 9.8 Tf [( gene)] TJ ET 0.267 0.267 0.267 rg BT 337.831 335.918 Td /F6 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 342.649 334.410 Td /F1 9.8 Tf [(. Cylindromas are benign appendageal tumours )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(occurring mainly on the scalp, but can occur on any hair bearing skin. The lesions typically present as painless, smooth pink )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(nodules, which may be either solitary or clustered together. They are slow-growing and vary in size from a few millimetres to )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(over six centimetres.)] TJ ET 0.965 0.965 0.965 rg 26.250 60.815 555.000 228.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 288.815 m 581.250 288.815 l 581.250 288.065 l 26.250 288.065 l f q 225.000 0 0 212.250 35.250 66.815 cm /I3 Do Q q 35.250 60.815 537.000 0.000 re W n Q Q q 15.000 684.354 577.500 53.646 re W n 0.271 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(CYLD)] TJ ET 0.267 0.267 0.267 rg BT 69.831 718.042 Td /F3 21.0 Tf [( GeneticTesting for Brooke-Spiegler Syndrome, Familial )] TJ ET BT 15.000 693.094 Td /F3 21.0 Tf [(Cylindromatosis and Multiple Familial Trichoepitheliomas)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F4 9.8 Tf [(February 19, 2015)] TJ ET BT 93.263 675.088 Td /F4 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 98.138 675.088 Td /F4 9.8 Tf [(Diagnostic)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Anna Dubois)] TJ ET 0.271 0.267 0.267 rg BT 82.069 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 87.490 663.247 Td /F1 9.8 Tf [(Valerie Wilson)] TJ ET 0.271 0.267 0.267 rg BT 149.792 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 155.213 663.247 Td /F1 9.8 Tf [(David Bourn)] TJ ET 0.271 0.267 0.267 rg BT 208.858 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 214.279 663.247 Td /F1 9.8 Tf [(Neil Rajan)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Dubois A, Wilson V, Bourn D, Rajan N. )] TJ ET BT 196.934 651.342 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 222.937 651.342 Td /F1 9.8 Tf [( GeneticTesting for Brooke-Spiegler Syndrome, Familial Cylindromatosis and )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Multiple Familial Trichoepitheliomas. PLOS Currents Evidence on Genomic Tests. 2015 Feb 19 . Edition 1. doi: )] TJ ET BT 26.250 627.533 Td /F1 9.8 Tf [(10.1371/currents.eogt.45c4e63dd43d62e12228cc5264d6a0db.)] TJ ET q 15.000 60.815 577.500 564.337 re W n 0.271 0.267 0.267 rg BT 26.250 598.430 Td /F6 12.0 Tf [(Abstract)] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(The clinical presentation of multiple, rare, skin appendage tumours called cylindromas has been attributed to germline mutations )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(in the tumour suppressor gene )] TJ ET BT 161.190 566.571 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 187.193 566.571 Td /F1 9.8 Tf [( \(OMIM 605018\). Brooke-Spiegler Syndrome \(BSS\), familial cylindromatosis \(FC\) and )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(multiple familial trichoepitheliomas \(MFT\) \(OMIM #605041, #132700, #601606 respectively\) differ due to the types of other skin )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(appendage tumour seen together with cylindroma, such as spiradenoma and trichoepithelioma. Previously thought to be )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(separate entities, they are now viewed as allelic variants with overlapping phenotypes, supported by mutation analysis of )] TJ ET BT 548.655 530.857 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(. The conditions display autosomal dominant inheritance and affected individuals develop multiple benign skin tumours most )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(commonly on the head and neck.)] TJ ET BT 26.250 487.643 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 52.253 487.643 Td /F1 9.8 Tf [( testing can be performed using PCR and Sanger sequencing for patients with:)] TJ ET BT 26.250 475.738 Td /F1 9.8 Tf [(1. Multiple cylindromas, spiradenomas or trichoepitheliomas.)] TJ ET BT 26.250 463.833 Td /F1 9.8 Tf [(2. A single cylindroma, spiradenoma or trichoepithelioma and an affected first-degree relative with any of these tumours.)] TJ ET BT 26.250 451.929 Td /F1 9.8 Tf [(3. An asymptomatic family member at 50% risk with a known mutation in the family.)] TJ ET BT 26.250 415.326 Td /F6 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 395.372 Td /F1 9.8 Tf [(Neil Rajan is a Wellcome Intermediate Fellow. The funders had no role in study design, data collection and analysis, decision to )] TJ ET BT 26.250 383.467 Td /F1 9.8 Tf [(publish, or preparation of the manuscript.)] TJ ET BT 26.250 354.365 Td /F6 12.0 Tf [(Clinical Phenotype)] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(BSS, FC and MFT arise from heterozygous mutations in the )] TJ ET BT 287.433 334.410 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 313.436 334.410 Td /F1 9.8 Tf [( gene)] TJ ET 0.267 0.267 0.267 rg BT 337.831 335.918 Td /F6 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 342.649 334.410 Td /F1 9.8 Tf [(. Cylindromas are benign appendageal tumours )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(occurring mainly on the scalp, but can occur on any hair bearing skin. The lesions typically present as painless, smooth pink )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(nodules, which may be either solitary or clustered together. They are slow-growing and vary in size from a few millimetres to )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(over six centimetres.)] TJ ET 0.965 0.965 0.965 rg 26.250 60.815 555.000 228.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 288.815 m 581.250 288.815 l 581.250 288.065 l 26.250 288.065 l f q 225.000 0 0 212.250 35.250 66.815 cm /I3 Do Q q 35.250 60.815 537.000 0.000 re W n Q Q q 225.000 0 0 212.250 35.250 66.815 cm /I3 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(1)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Evidence on Genomic Tests)] TJ ET Q endstream endobj 8 0 obj << /Type /Font /Subtype /Type1 /Name /F1 /BaseFont /Helvetica /Encoding /WinAnsiEncoding >> endobj 9 0 obj << /Type /Font /Subtype /Type1 /Name /F2 /BaseFont /Times-BoldItalic /Encoding /WinAnsiEncoding >> endobj 10 0 obj << /Type /Font /Subtype /Type1 /Name /F3 /BaseFont /Times-Bold /Encoding /WinAnsiEncoding >> endobj 11 0 obj << /Type /Font /Subtype /Type1 /Name /F4 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Td /F1 9.8 Tf [(Several well-circumscribed, pink, nodular cylindromas with arborizing blood vessels on the surface, occurring on the scalp )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(of a patient with BSS.)] TJ ET Q BT 26.250 695.849 Td /F1 9.8 Tf [(Spiradenomas often occur in conjunction with cylindromas in BSS, but tend to be painful rather than painless. They can present )] TJ ET BT 26.250 683.944 Td /F1 9.8 Tf [(as a dermal nodule, often with a blue/black appearance.)] TJ ET 0.965 0.965 0.965 rg 26.250 385.172 555.000 288.891 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 674.063 m 581.250 674.063 l 581.250 673.313 l 26.250 673.313 l f 26.250 385.172 m 581.250 385.172 l 581.250 385.922 l 26.250 385.922 l f q 225.000 0 0 222.750 35.250 441.563 cm /I4 Do Q q 35.250 396.422 537.000 39.141 re W n 0.271 0.267 0.267 rg BT 35.250 426.039 Td /F6 9.8 Tf [(Fig. 2: Spiradenoma)] TJ ET BT 35.250 406.669 Td /F1 9.8 Tf [(Nodular lesion with characteristic blue/black appearance.)] TJ ET Q BT 26.250 368.148 Td /F1 9.8 Tf [(Definitive diagnosis of cylindromas and spiradenomas requires histopathological examination of an excised lesion. )] TJ ET BT 26.250 356.244 Td /F1 9.8 Tf [(Histopathologically, cylindromas consist of nests of basaloid cells arranged into nodules that resemble a cylinder in cross )] TJ ET BT 26.250 344.339 Td /F1 9.8 Tf [(section. These form an irregular pattern, often a likened to a jigsaw.)] TJ ET 0.965 0.965 0.965 rg 26.250 103.081 555.000 231.377 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 334.458 m 581.250 334.458 l 581.250 333.708 l 26.250 333.708 l f 26.250 103.081 m 581.250 103.081 l 581.250 103.831 l 26.250 103.831 l f q 225.000 0 0 151.500 35.250 173.208 cm /I5 Do Q q 35.250 114.331 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 157.684 Td /F6 9.8 Tf [(Fig. 3: Histology of a cylindroma)] TJ ET BT 35.250 138.314 Td /F1 9.8 Tf [(The typical appearance of a cylindroma at low power \(10x\), consisting of well-defined nests of basaloid cells separated by )] TJ ET BT 35.250 124.578 Td /F1 9.8 Tf [(an eosinophilic basement membrane.)] TJ ET Q BT 26.250 86.057 Td /F1 9.8 Tf [(These tumours are rare in the general population, and a histology result should raise the suspicion of a germline )] TJ ET BT 511.810 86.057 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 537.813 86.057 Td /F1 9.8 Tf [( mutation )] TJ ET BT 26.250 74.152 Td /F1 9.8 Tf [(in a young person.)] TJ ET BT 26.250 54.747 Td /F1 9.8 Tf [(A diagnosis of FC or MFT is prompted by the dominant tumour type being cylindroma or trichoepithelioma respectively. BSS )] TJ ET BT 26.250 42.843 Td /F1 9.8 Tf [(presents with a variety of skin appendage tumours including cylindromas, spiradenomas and trichoepitheliomas. The distinction )] TJ ET Q q 15.000 28.557 577.500 748.443 re W n 0.965 0.965 0.965 rg 26.250 712.873 555.000 64.127 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 712.873 m 581.250 712.873 l 581.250 713.623 l 26.250 713.623 l f q 35.250 724.123 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F6 9.8 Tf [(Fig. 1: Cylindroma)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(Several well-circumscribed, pink, nodular cylindromas with arborizing blood vessels on the surface, occurring on the scalp )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(of a patient with BSS.)] TJ ET Q BT 26.250 695.849 Td /F1 9.8 Tf [(Spiradenomas often occur in conjunction with cylindromas in BSS, but tend to be painful rather than painless. They can present )] TJ ET BT 26.250 683.944 Td /F1 9.8 Tf [(as a dermal nodule, often with a blue/black appearance.)] TJ ET 0.965 0.965 0.965 rg 26.250 385.172 555.000 288.891 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 674.063 m 581.250 674.063 l 581.250 673.313 l 26.250 673.313 l f 26.250 385.172 m 581.250 385.172 l 581.250 385.922 l 26.250 385.922 l f q 225.000 0 0 222.750 35.250 441.563 cm /I4 Do Q q 35.250 396.422 537.000 39.141 re W n 0.271 0.267 0.267 rg BT 35.250 426.039 Td /F6 9.8 Tf [(Fig. 2: Spiradenoma)] TJ ET BT 35.250 406.669 Td /F1 9.8 Tf [(Nodular lesion with characteristic blue/black appearance.)] TJ ET Q BT 26.250 368.148 Td /F1 9.8 Tf [(Definitive diagnosis of cylindromas and spiradenomas requires histopathological examination of an excised lesion. )] TJ ET BT 26.250 356.244 Td /F1 9.8 Tf [(Histopathologically, cylindromas consist of nests of basaloid cells arranged into nodules that resemble a cylinder in cross )] TJ ET BT 26.250 344.339 Td /F1 9.8 Tf [(section. These form an irregular pattern, often a likened to a jigsaw.)] TJ ET 0.965 0.965 0.965 rg 26.250 103.081 555.000 231.377 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 334.458 m 581.250 334.458 l 581.250 333.708 l 26.250 333.708 l f 26.250 103.081 m 581.250 103.081 l 581.250 103.831 l 26.250 103.831 l f q 225.000 0 0 151.500 35.250 173.208 cm /I5 Do Q q 35.250 114.331 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 157.684 Td /F6 9.8 Tf [(Fig. 3: Histology of a cylindroma)] TJ ET BT 35.250 138.314 Td /F1 9.8 Tf [(The typical appearance of a cylindroma at low power \(10x\), consisting of well-defined nests of basaloid cells separated by )] TJ ET BT 35.250 124.578 Td /F1 9.8 Tf [(an eosinophilic basement membrane.)] TJ ET Q BT 26.250 86.057 Td /F1 9.8 Tf [(These tumours are rare in the general population, and a histology result should raise the suspicion of a germline )] TJ ET BT 511.810 86.057 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 537.813 86.057 Td /F1 9.8 Tf [( mutation )] TJ ET BT 26.250 74.152 Td /F1 9.8 Tf [(in a young person.)] TJ ET BT 26.250 54.747 Td /F1 9.8 Tf [(A diagnosis of FC or MFT is prompted by the dominant tumour type being cylindroma or trichoepithelioma respectively. BSS )] TJ ET BT 26.250 42.843 Td /F1 9.8 Tf [(presents with a variety of skin appendage tumours including cylindromas, spiradenomas and trichoepitheliomas. The distinction )] TJ ET Q q 15.000 28.557 577.500 748.443 re W n 0.965 0.965 0.965 rg 26.250 712.873 555.000 64.127 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 712.873 m 581.250 712.873 l 581.250 713.623 l 26.250 713.623 l f q 35.250 724.123 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F6 9.8 Tf [(Fig. 1: Cylindroma)] TJ ET BT 35.250 748.106 Td /F1 9.8 Tf [(Several well-circumscribed, pink, nodular cylindromas with arborizing blood vessels on the surface, occurring on the scalp )] TJ ET BT 35.250 734.370 Td /F1 9.8 Tf [(of a patient with BSS.)] TJ ET Q BT 26.250 695.849 Td /F1 9.8 Tf [(Spiradenomas often occur in conjunction with cylindromas in BSS, but tend to be painful rather than painless. They can present )] TJ ET BT 26.250 683.944 Td /F1 9.8 Tf [(as a dermal nodule, often with a blue/black appearance.)] TJ ET 0.965 0.965 0.965 rg 26.250 385.172 555.000 288.891 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 674.063 m 581.250 674.063 l 581.250 673.313 l 26.250 673.313 l f 26.250 385.172 m 581.250 385.172 l 581.250 385.922 l 26.250 385.922 l f q 225.000 0 0 222.750 35.250 441.563 cm /I4 Do Q q 35.250 396.422 537.000 39.141 re W n 0.271 0.267 0.267 rg BT 35.250 426.039 Td /F6 9.8 Tf [(Fig. 2: Spiradenoma)] TJ ET BT 35.250 406.669 Td /F1 9.8 Tf [(Nodular lesion with characteristic blue/black appearance.)] TJ ET Q BT 26.250 368.148 Td /F1 9.8 Tf [(Definitive diagnosis of cylindromas and spiradenomas requires histopathological examination of an excised lesion. )] TJ ET BT 26.250 356.244 Td /F1 9.8 Tf [(Histopathologically, cylindromas consist of nests of basaloid cells arranged into nodules that resemble a cylinder in cross )] TJ ET BT 26.250 344.339 Td /F1 9.8 Tf [(section. These form an irregular pattern, often a likened to a jigsaw.)] TJ ET 0.965 0.965 0.965 rg 26.250 103.081 555.000 231.377 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 334.458 m 581.250 334.458 l 581.250 333.708 l 26.250 333.708 l f 26.250 103.081 m 581.250 103.081 l 581.250 103.831 l 26.250 103.831 l f q 225.000 0 0 151.500 35.250 173.208 cm /I5 Do Q q 35.250 114.331 537.000 52.877 re W n 0.271 0.267 0.267 rg BT 35.250 157.684 Td /F6 9.8 Tf [(Fig. 3: Histology of a cylindroma)] TJ ET BT 35.250 138.314 Td /F1 9.8 Tf [(The typical appearance of a cylindroma at low power \(10x\), consisting of well-defined nests of basaloid cells separated by )] TJ ET BT 35.250 124.578 Td /F1 9.8 Tf [(an eosinophilic basement membrane.)] TJ ET Q BT 26.250 86.057 Td /F1 9.8 Tf [(These tumours are rare in the general population, and a histology result should raise the suspicion of a germline )] TJ ET BT 511.810 86.057 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 537.813 86.057 Td /F1 9.8 Tf [( mutation )] TJ ET BT 26.250 74.152 Td /F1 9.8 Tf [(in a young person.)] TJ ET BT 26.250 54.747 Td /F1 9.8 Tf [(A diagnosis of FC or MFT is prompted by the dominant tumour type being cylindroma or trichoepithelioma respectively. BSS )] TJ ET BT 26.250 42.843 Td /F1 9.8 Tf [(presents with a variety of skin appendage tumours including cylindromas, spiradenomas and trichoepitheliomas. 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'}/Q2\l7 c?AD. !b B |HׯM[h-㈨*`qϬMTuGc+Fny ϧqpjf~xƶUWPKN:3 Myan&kg3ֳ5kxh+hfp1Ϯ;ׅG>HIk蕯wGju?#63?QkүimIfDۇP~ZRfXncyu,m($_1QGzxYվ˞v15҃o&ѺB\c?kӼuYeق`Һ2+[%koOaN S3z> $o;{Urb1ʻ8aTsfUBb +BX)(nI&e={pzR:Qo͞^*-HݪJ4k@0,{g+%5oLUϑf nmq?z[O/R,r#0ށ_98Du[].Iv*)9ԯ$$U$mzsg=^$fcʃ o-t~$q0?:ƜowVPrpK0jq\X\!ԯ<`yɪƝsq >H*ˈ 'j_ ޏu6:7iAp'vK]P$Z|:.j72mi.~ZL_Y6"m*VOK-_ݧ$_;fk:^rŲ+Iyi8z[VqKw#Oyl2mF:O5[,3uOB9PHZMBX.Z('X'wsN9%ltoN)4Ń}[-JAKXy;~$K/j"kx',y Ce cZℼXoD@2\úqei o%K4~ĝ܌c[ڤitm*v=}uskmҗ]{c<%{e1i IpFN9VIx"3hS2Bj`2Agk}_QSjtؽx{ŞmͤP,6QRJXr1k gH%ҡHHyvs=^s,!o.@u gyRSI'g^30;7 8÷:URI ZF` S|r}tJ㈗%\ʨv_Ο^k:ظ0G!U='Uen۷nG^)M5(i%rx8ǮyQ\bpXt u|M9 5eA&<;qb{׫Zֵ[è%,Yw&ƒy8506liYnsRU&,Ы]m-'Xe(%n Ҽwmm]Ӄo=VL) n?y^x5mEg "8TûJ涼 vnXGtkʠ 6C=q]|#xc:vQURB)!A$}\u()i^Ά=O}mO' 2M&H\ I>C`7A! s߈c|H} ƝImm khB4C-/<@qVKauA0<33KCnvTVRkAzF$΅Tu,^ykxkK΁kgl{HFe}==pXx<<^Sӽ_M7v0Voz[wb|zZ֛ su$enP`;tk Èrf sK;hLh85dV0oxKe)J {&b c (r#8iٹ +y<@?ckqé1&HB~sӏZ]Cj-mf۬r0nO_`KWZ?>SeMEF[m^& uO.kem !͔0P99iLqGkh WUۓ0 " 5ZKkDi$r~*kI ֎eW{%cFWLL'3rWztZ+^3P[ߣ#Ҵ]+\nOynM^"Jі;NGc{Ժˢs=2-&Mk;K-&٭b~y6Y<,흡I<{_E{uaeQ>[aqJާ+6iGNZ_ߦhi~/ZCy "A^QFk&7w \#bdgֽ}A8-YkL.v"GbCswf6Z| H+c_8A{qOO壷mWwq^KOc5F[McݫiM+[oCWZB㺚X߆[(#NIn5*e'>R!*Zi\#b׊)x=}+SB罻'[8;kfl^SGiIw\}]zÐy@PS޽c#xvKm5[g^5'}=.![挫=G*GP~OB=[:[Tc=+ۿgIu>g VYyT~9+7Kfs ,5τ.#8aΊ^ZZ_kw`vBWDAtRH#Yjɴp0űq_kjUN9c A0[k9Uo0l'&D;s0lWGq ]q>?K.NZy-=/ĚܺlW %X1%€15ĬLNiѮ z7%(ҩf|)h~fdQ/2Iv8@AUR@א7\6ƛwXʟw Yd}yZv=_VEw~ь|mpp+b4[}@ZDo-cheĭ}3ks\~U,<5G~m/TQHw/]v v㹵 IclUr )|9\i3o!+Է2I^DŽm. 7729JϾf9aq]UPF$dmx}&%hk-:s>&GIW8_=|NK ͢3,ʊ+d|^zK2G_A߆dhX#!=OҺ~iNkuס݁3N_xu}6WⴖV-t$Bk9O|~iN\h>E"'?NzV4-Kᣐi_;p2Y5)ѭk_%ϧsjΛXj/ֵ HGyی0Ʋh.Ö˽w^V?~\N9Qz:r{pZY;]2i '_*r %{ѭ))n=q]/ /:Ke-wQwzW>dp|\ _GbkZXٯw:BA c_YU֩j_E4JˌaCx 澐xvVd1(ޑˎs[ۘMjP}M6d5 0J3Ҿ!eUR]֫WݗqrLxNH?i7Woo L40%RI, e&K\ɥ\1#PMł*Ǯs5Z;K-5ogdY3ew>`W qqZBpEJcKT72{s_O*pm>U[gzuftzfk4mޱ撂9!"d^d%rXZghjsk}nR3یg􏪍~kr^[a8Qa-Tm $`YҖt]r]+#?giu>}; ܅KӐo{gt/&Ѧ/*cz`@#sx뺕&33H79$ry?*U5RzWS$y.}ZKߡCxoEkkK)G`q[ `כ]Uel |%0Jm>a(XŜ8@0Vf<{?^kyk JHa)$K(R^|9byʟ]#Ю8Mv=Tm7ƼƳŋ6mod!m_gw|?4CQԦȳ((0zbѻFHQʜ\:Y1(] GHܼ9t"SvkjoK>:f rhbSgݐ:u6L8sg!Fq9zbKq̋,m )y UռQ<,KP% `HOYqVR4\姗AM98+=CuMmmSHkxɲ ;w>^8^ӯlnbәBřr1EG,Iw}t|k~-?*%A&LtyoUW_v._jǝ:RznVڴ>S1J>W2L,ӞyV9qxL U?461ȖW]N>QM/:L\ځ|y9\)NڥӿKשЌJ~*+4ʯzW_Zo(>'ڽܢ+I*W]}s(SS/{+ n>7o/7J<   5N6rCoN," E6H* \s~M{2NsZ+שU.gg^ gدt:}ēyrUod^oxEmpg R |ib c}Mo~73M{E$F2͞=hS.JկOemYmkKh-ABnx#k}2}GMṶmͪil4S;T ­}V'RFҾ,Ӥ{!m٠uBk;dj8~m'IۯٹeRs9=u| xN+PcHK(ZDc<>`U> endobj 86 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/genomictests/files/2014/06/Figure-1-b.jpg) >> endobj 87 0 obj << /Type /Annot /Subtype /Link /A 88 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 173.2080 260.2500 324.7080 ] >> endobj 88 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/genomictests/files/2014/06/Figure-1c.jpg) >> endobj 89 0 obj << /Type /Annot /Subtype /Link /A 90 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 441.5632 260.2500 664.3132 ] >> endobj 90 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/genomictests/files/2014/06/Figure-1-b.jpg) >> endobj 91 0 obj << /Type /Annot /Subtype /Link /A 92 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 173.2080 260.2500 324.7080 ] >> endobj 92 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/genomictests/files/2014/06/Figure-1c.jpg) >> endobj 93 0 obj << /Type /Page /Parent 3 0 R /Annots [ 95 0 R 97 0 R 99 0 R 101 0 R 103 0 R 105 0 R 107 0 R 109 0 R 111 0 R 113 0 R 115 0 R 117 0 R 119 0 R 121 0 R 123 0 R 125 0 R 127 0 R 129 0 R 131 0 R 133 0 R 135 0 R 137 0 R 139 0 R 141 0 R ] /Contents 94 0 R >> endobj 94 0 obj << /Length 24158 >> stream 0.271 0.267 0.267 rg q 15.000 27.797 577.500 749.203 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(made between the different conditions hence depends on the combination of tumour types identified. These divisions are not )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(thought to be useful in the clinic in terms of prognostic information or counselling patients, and hence the term )] TJ ET BT 501.524 755.571 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 527.527 755.571 Td /F1 9.8 Tf [( cutaneous )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(syndrome has been proposed)] TJ ET 0.267 0.267 0.267 rg BT 155.233 745.174 Td /F6 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 160.051 743.667 Td /F1 9.8 Tf [( . The timing of tumour onset is usually in adolescence, but can occur from after adrenarche in )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(childhood, up to the 4)] TJ ET BT 119.480 735.650 Td /F1 8.7 Tf [(th)] TJ ET BT 126.708 731.762 Td /F1 9.8 Tf [( decade. The skin appendage tumours have a predilection for the face and scalp, although also affect )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(the trunk, most commonly in hair-bearing areas)] TJ ET 0.267 0.267 0.267 rg BT 229.986 721.364 Td /F6 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 234.805 719.857 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(The morbidity associated with skin appendage tumours in these conditions can be substantial. The tumours are disfiguring, can )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(be painful and occur in multiple sites. Affected individuals face repeated episodes of surgery to remove lesions, and in some )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(cases this may culminate in removal of the entire scalp)] TJ ET 0.267 0.267 0.267 rg BT 262.502 678.150 Td /F6 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 267.321 676.643 Td /F1 9.8 Tf [( . Patients may request surgery when tumours are painful, ulcerated, )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(bleeding, unsightly or causing sexual dysfunction)] TJ ET 0.267 0.267 0.267 rg BT 237.601 666.245 Td /F6 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 242.419 664.738 Td /F1 9.8 Tf [( . In affected families, genetic testing allows individuals to ascertain their own )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(risk and to use the information for family planning purposes.)] TJ ET BT 26.250 616.231 Td /F6 12.0 Tf [(Test Description)] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(Blood in EDTA is the preferred tissue but buccal swabs, mouthwash samples or solid tissue can also be tested. The testing )] TJ ET BT 26.250 584.372 Td /F1 9.8 Tf [(protocol involves PCR amplification of exons 4-20 of )] TJ ET BT 254.381 584.372 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 280.384 584.372 Td /F1 9.8 Tf [( in a total of 18 amplicons. In addition to the exonic sequence at least )] TJ ET BT 26.250 572.467 Td /F1 9.8 Tf [(10bp of flanking intronic sequence is captured at the 5 and 3 end of each exon. Following PCR amplification each amplicon is )] TJ ET BT 26.250 560.562 Td /F1 9.8 Tf [(sequenced by bi-directional fluorescent Sanger sequencing and the data analysed using the current version of Mutation )] TJ ET BT 26.250 548.658 Td /F1 9.8 Tf [(Surveyor software.)] TJ ET BT 26.250 512.055 Td /F6 12.0 Tf [(Public Health Importance)] TJ ET BT 26.250 492.101 Td /F1 9.8 Tf [(The estimated prevalence of )] TJ ET BT 151.976 492.101 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 177.980 492.101 Td /F1 9.8 Tf [( mutations in the UK population is 1:100000, although this is difficult to accurately determine. )] TJ ET BT 26.250 480.196 Td /F1 9.8 Tf [(The penetrance in terms of tumour development in those with a mutation in )] TJ ET BT 352.485 480.196 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 378.488 480.196 Td /F1 9.8 Tf [( is estimated to be close to 100%. Most cases )] TJ ET BT 26.250 468.291 Td /F1 9.8 Tf [(of BSS, FC and MFT result from autosomal dominant inheritance, although sporadic cases can also occur.)] TJ ET BT 26.250 448.887 Td /F1 9.8 Tf [(A genetic test result allows an individual to make decisions relating to family planning. It can also be useful to inform treatment )] TJ ET BT 26.250 436.982 Td /F1 9.8 Tf [(planning. Patients with a )] TJ ET BT 134.641 436.982 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 160.644 436.982 Td /F1 9.8 Tf [( mutation may be offered the opportunity to enrol into clinical trials. )] TJ ET BT 450.024 436.982 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 478.738 436.982 Td /F1 9.8 Tf [(encodes a )] TJ ET BT 26.250 425.077 Td /F1 9.8 Tf [(deubiquitinating enzyme that negatively regulates the nuclear factor-kappa beta pathway. A clinical trial using topical salicylic )] TJ ET BT 26.250 413.172 Td /F1 9.8 Tf [(acid was not promising)] TJ ET 0.267 0.267 0.267 rg BT 125.407 414.680 Td /F6 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 130.226 413.172 Td /F1 9.8 Tf [( . More recently gene expression profiling of tumours in patients with germline )] TJ ET BT 467.274 413.172 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 493.277 413.172 Td /F1 9.8 Tf [( mutations have )] TJ ET BT 26.250 401.268 Td /F1 9.8 Tf [(shown dysregulated tropomyosin kinase \(TRK\) signalling, and treatment with lestaurtinib, a TRK inhibitor reduced growth of )] TJ ET BT 26.250 389.363 Td /F1 9.8 Tf [(cells established from )] TJ ET BT 122.697 389.363 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 151.411 389.363 Td /F1 9.8 Tf [(mutant tumours in vitro)] TJ ET 0.267 0.267 0.267 rg BT 250.568 390.870 Td /F6 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 255.387 389.363 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 352.760 Td /F6 12.0 Tf [(Published reviews, recommendations and guidelines)] TJ ET BT 26.250 332.806 Td /F1 9.8 Tf [(Systematic evidence reviews: None identified)] TJ ET BT 26.250 313.401 Td /F1 9.8 Tf [(Recommendations by independent groups: UK GTN Gene dossier)] TJ ET BT 26.250 293.997 Td /F1 9.8 Tf [(Guidelines by professional groups: None identified)] TJ ET BT 26.250 257.394 Td /F6 12.0 Tf [(Evidence Overview)] TJ ET BT 26.250 237.440 Td /F6 9.8 Tf [(Analytic validity:)] TJ ET BT 26.250 218.035 Td /F1 9.8 Tf [(The testing methodology involves bi-directional fluorescent DNA sequencing of all coding exons of CYLD \(exons 4-20, exonic )] TJ ET BT 26.250 206.130 Td /F1 9.8 Tf [(sequence plus at least 10bp at the 5 and 3 of each intron\). This method would be expected to detect >99% of mutations )] TJ ET BT 26.250 194.226 Td /F1 9.8 Tf [(within the coding region/splice sites, excluding duplications and large deletions. Large deletions have been reported to affect a )] TJ ET BT 26.250 182.321 Td /F1 9.8 Tf [(minority of patients that are mutation negative following Sanger sequencing.)] TJ ET 0.267 0.267 0.267 rg BT 353.577 183.828 Td /F6 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 358.396 182.321 Td /F1 9.8 Tf [( cDNA testing is also carried out where )] TJ ET BT 26.250 170.416 Td /F1 9.8 Tf [(appropriate. The generic techniques are well established in the CPA-accredited Northern Genetics Service laboratory.)] TJ ET BT 26.250 151.011 Td /F6 9.8 Tf [(Validation:)] TJ ET BT 26.250 131.607 Td /F1 9.8 Tf [(The testing protocol was validated in confirming the findings of the research study described below.)] TJ ET BT 26.250 112.202 Td /F6 9.8 Tf [(Analytic sensitivity:)] TJ ET BT 26.250 92.797 Td /F1 9.8 Tf [(The analytic sensitivity and specificity are close to 100% for the techniques used.)] TJ ET BT 26.250 73.392 Td /F6 9.8 Tf [(Clinical validity:)] TJ ET BT 26.250 53.988 Td /F1 9.8 Tf [(A study investigating the mutational spectrum of )] TJ ET BT 235.972 53.988 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 264.686 53.988 Td /F1 9.8 Tf [(and genotype-phenotype correlation)] TJ ET 0.267 0.267 0.267 rg BT 420.774 55.495 Td /F6 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 425.593 53.988 Td /F1 9.8 Tf [( tested a total of 47 samples from )] TJ ET BT 26.250 42.083 Td /F1 9.8 Tf [(25 families exhibiting BSS, MFT or FC phenotypes. Of these families, 13 had clinical features of BSS, three of FC and nine of )] TJ ET Q q 15.000 27.797 577.500 749.203 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(made between the different conditions hence depends on the combination of tumour types identified. These divisions are not )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(thought to be useful in the clinic in terms of prognostic information or counselling patients, and hence the term )] TJ ET BT 501.524 755.571 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 527.527 755.571 Td /F1 9.8 Tf [( cutaneous )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(syndrome has been proposed)] TJ ET 0.267 0.267 0.267 rg BT 155.233 745.174 Td /F6 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 160.051 743.667 Td /F1 9.8 Tf [( . The timing of tumour onset is usually in adolescence, but can occur from after adrenarche in )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(childhood, up to the 4)] TJ ET BT 119.480 735.650 Td /F1 8.7 Tf [(th)] TJ ET BT 126.708 731.762 Td /F1 9.8 Tf [( decade. The skin appendage tumours have a predilection for the face and scalp, although also affect )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(the trunk, most commonly in hair-bearing areas)] TJ ET 0.267 0.267 0.267 rg BT 229.986 721.364 Td /F6 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 234.805 719.857 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(The morbidity associated with skin appendage tumours in these conditions can be substantial. The tumours are disfiguring, can )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(be painful and occur in multiple sites. Affected individuals face repeated episodes of surgery to remove lesions, and in some )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(cases this may culminate in removal of the entire scalp)] TJ ET 0.267 0.267 0.267 rg BT 262.502 678.150 Td /F6 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 267.321 676.643 Td /F1 9.8 Tf [( . Patients may request surgery when tumours are painful, ulcerated, )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(bleeding, unsightly or causing sexual dysfunction)] TJ ET 0.267 0.267 0.267 rg BT 237.601 666.245 Td /F6 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 242.419 664.738 Td /F1 9.8 Tf [( . In affected families, genetic testing allows individuals to ascertain their own )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(risk and to use the information for family planning purposes.)] TJ ET BT 26.250 616.231 Td /F6 12.0 Tf [(Test Description)] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(Blood in EDTA is the preferred tissue but buccal swabs, mouthwash samples or solid tissue can also be tested. The testing )] TJ ET BT 26.250 584.372 Td /F1 9.8 Tf [(protocol involves PCR amplification of exons 4-20 of )] TJ ET BT 254.381 584.372 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 280.384 584.372 Td /F1 9.8 Tf [( in a total of 18 amplicons. In addition to the exonic sequence at least )] TJ ET BT 26.250 572.467 Td /F1 9.8 Tf [(10bp of flanking intronic sequence is captured at the 5 and 3 end of each exon. Following PCR amplification each amplicon is )] TJ ET BT 26.250 560.562 Td /F1 9.8 Tf [(sequenced by bi-directional fluorescent Sanger sequencing and the data analysed using the current version of Mutation )] TJ ET BT 26.250 548.658 Td /F1 9.8 Tf [(Surveyor software.)] TJ ET BT 26.250 512.055 Td /F6 12.0 Tf [(Public Health Importance)] TJ ET BT 26.250 492.101 Td /F1 9.8 Tf [(The estimated prevalence of )] TJ ET BT 151.976 492.101 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 177.980 492.101 Td /F1 9.8 Tf [( mutations in the UK population is 1:100000, although this is difficult to accurately determine. )] TJ ET BT 26.250 480.196 Td /F1 9.8 Tf [(The penetrance in terms of tumour development in those with a mutation in )] TJ ET BT 352.485 480.196 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 378.488 480.196 Td /F1 9.8 Tf [( is estimated to be close to 100%. Most cases )] TJ ET BT 26.250 468.291 Td /F1 9.8 Tf [(of BSS, FC and MFT result from autosomal dominant inheritance, although sporadic cases can also occur.)] TJ ET BT 26.250 448.887 Td /F1 9.8 Tf [(A genetic test result allows an individual to make decisions relating to family planning. It can also be useful to inform treatment )] TJ ET BT 26.250 436.982 Td /F1 9.8 Tf [(planning. Patients with a )] TJ ET BT 134.641 436.982 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 160.644 436.982 Td /F1 9.8 Tf [( mutation may be offered the opportunity to enrol into clinical trials. )] TJ ET BT 450.024 436.982 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 478.738 436.982 Td /F1 9.8 Tf [(encodes a )] TJ ET BT 26.250 425.077 Td /F1 9.8 Tf [(deubiquitinating enzyme that negatively regulates the nuclear factor-kappa beta pathway. A clinical trial using topical salicylic )] TJ ET BT 26.250 413.172 Td /F1 9.8 Tf [(acid was not promising)] TJ ET 0.267 0.267 0.267 rg BT 125.407 414.680 Td /F6 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 130.226 413.172 Td /F1 9.8 Tf [( . More recently gene expression profiling of tumours in patients with germline )] TJ ET BT 467.274 413.172 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 493.277 413.172 Td /F1 9.8 Tf [( mutations have )] TJ ET BT 26.250 401.268 Td /F1 9.8 Tf [(shown dysregulated tropomyosin kinase \(TRK\) signalling, and treatment with lestaurtinib, a TRK inhibitor reduced growth of )] TJ ET BT 26.250 389.363 Td /F1 9.8 Tf [(cells established from )] TJ ET BT 122.697 389.363 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 151.411 389.363 Td /F1 9.8 Tf [(mutant tumours in vitro)] TJ ET 0.267 0.267 0.267 rg BT 250.568 390.870 Td /F6 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 255.387 389.363 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 352.760 Td /F6 12.0 Tf [(Published reviews, recommendations and guidelines)] TJ ET BT 26.250 332.806 Td /F1 9.8 Tf [(Systematic evidence reviews: None identified)] TJ ET BT 26.250 313.401 Td /F1 9.8 Tf [(Recommendations by independent groups: UK GTN Gene dossier)] TJ ET BT 26.250 293.997 Td /F1 9.8 Tf [(Guidelines by professional groups: None identified)] TJ ET BT 26.250 257.394 Td /F6 12.0 Tf [(Evidence Overview)] TJ ET BT 26.250 237.440 Td /F6 9.8 Tf [(Analytic validity:)] TJ ET BT 26.250 218.035 Td /F1 9.8 Tf [(The testing methodology involves bi-directional fluorescent DNA sequencing of all coding exons of CYLD \(exons 4-20, exonic )] TJ ET BT 26.250 206.130 Td /F1 9.8 Tf [(sequence plus at least 10bp at the 5 and 3 of each intron\). This method would be expected to detect >99% of mutations )] TJ ET BT 26.250 194.226 Td /F1 9.8 Tf [(within the coding region/splice sites, excluding duplications and large deletions. Large deletions have been reported to affect a )] TJ ET BT 26.250 182.321 Td /F1 9.8 Tf [(minority of patients that are mutation negative following Sanger sequencing.)] TJ ET 0.267 0.267 0.267 rg BT 353.577 183.828 Td /F6 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 358.396 182.321 Td /F1 9.8 Tf [( cDNA testing is also carried out where )] TJ ET BT 26.250 170.416 Td /F1 9.8 Tf [(appropriate. The generic techniques are well established in the CPA-accredited Northern Genetics Service laboratory.)] TJ ET BT 26.250 151.011 Td /F6 9.8 Tf [(Validation:)] TJ ET BT 26.250 131.607 Td /F1 9.8 Tf [(The testing protocol was validated in confirming the findings of the research study described below.)] TJ ET BT 26.250 112.202 Td /F6 9.8 Tf [(Analytic sensitivity:)] TJ ET BT 26.250 92.797 Td /F1 9.8 Tf [(The analytic sensitivity and specificity are close to 100% for the techniques used.)] TJ ET BT 26.250 73.392 Td /F6 9.8 Tf [(Clinical validity:)] TJ ET BT 26.250 53.988 Td /F1 9.8 Tf [(A study investigating the mutational spectrum of )] TJ ET BT 235.972 53.988 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 264.686 53.988 Td /F1 9.8 Tf [(and genotype-phenotype correlation)] TJ ET 0.267 0.267 0.267 rg BT 420.774 55.495 Td /F6 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 425.593 53.988 Td /F1 9.8 Tf [( tested a total of 47 samples from )] TJ ET BT 26.250 42.083 Td /F1 9.8 Tf [(25 families exhibiting BSS, MFT or FC phenotypes. Of these families, 13 had clinical features of BSS, three of FC and nine of )] TJ ET Q q 15.000 27.797 577.500 749.203 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(made between the different conditions hence depends on the combination of tumour types identified. These divisions are not )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(thought to be useful in the clinic in terms of prognostic information or counselling patients, and hence the term )] TJ ET BT 501.524 755.571 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 527.527 755.571 Td /F1 9.8 Tf [( cutaneous )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(syndrome has been proposed)] TJ ET 0.267 0.267 0.267 rg BT 155.233 745.174 Td /F6 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 160.051 743.667 Td /F1 9.8 Tf [( . The timing of tumour onset is usually in adolescence, but can occur from after adrenarche in )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(childhood, up to the 4)] TJ ET BT 119.480 735.650 Td /F1 8.7 Tf [(th)] TJ ET BT 126.708 731.762 Td /F1 9.8 Tf [( decade. The skin appendage tumours have a predilection for the face and scalp, although also affect )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(the trunk, most commonly in hair-bearing areas)] TJ ET 0.267 0.267 0.267 rg BT 229.986 721.364 Td /F6 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 234.805 719.857 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(The morbidity associated with skin appendage tumours in these conditions can be substantial. The tumours are disfiguring, can )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(be painful and occur in multiple sites. Affected individuals face repeated episodes of surgery to remove lesions, and in some )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(cases this may culminate in removal of the entire scalp)] TJ ET 0.267 0.267 0.267 rg BT 262.502 678.150 Td /F6 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 267.321 676.643 Td /F1 9.8 Tf [( . Patients may request surgery when tumours are painful, ulcerated, )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(bleeding, unsightly or causing sexual dysfunction)] TJ ET 0.267 0.267 0.267 rg BT 237.601 666.245 Td /F6 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 242.419 664.738 Td /F1 9.8 Tf [( . In affected families, genetic testing allows individuals to ascertain their own )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(risk and to use the information for family planning purposes.)] TJ ET BT 26.250 616.231 Td /F6 12.0 Tf [(Test Description)] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(Blood in EDTA is the preferred tissue but buccal swabs, mouthwash samples or solid tissue can also be tested. The testing )] TJ ET BT 26.250 584.372 Td /F1 9.8 Tf [(protocol involves PCR amplification of exons 4-20 of )] TJ ET BT 254.381 584.372 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 280.384 584.372 Td /F1 9.8 Tf [( in a total of 18 amplicons. In addition to the exonic sequence at least )] TJ ET BT 26.250 572.467 Td /F1 9.8 Tf [(10bp of flanking intronic sequence is captured at the 5 and 3 end of each exon. Following PCR amplification each amplicon is )] TJ ET BT 26.250 560.562 Td /F1 9.8 Tf [(sequenced by bi-directional fluorescent Sanger sequencing and the data analysed using the current version of Mutation )] TJ ET BT 26.250 548.658 Td /F1 9.8 Tf [(Surveyor software.)] TJ ET BT 26.250 512.055 Td /F6 12.0 Tf [(Public Health Importance)] TJ ET BT 26.250 492.101 Td /F1 9.8 Tf [(The estimated prevalence of )] TJ ET BT 151.976 492.101 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 177.980 492.101 Td /F1 9.8 Tf [( mutations in the UK population is 1:100000, although this is difficult to accurately determine. )] TJ ET BT 26.250 480.196 Td /F1 9.8 Tf [(The penetrance in terms of tumour development in those with a mutation in )] TJ ET BT 352.485 480.196 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 378.488 480.196 Td /F1 9.8 Tf [( is estimated to be close to 100%. Most cases )] TJ ET BT 26.250 468.291 Td /F1 9.8 Tf [(of BSS, FC and MFT result from autosomal dominant inheritance, although sporadic cases can also occur.)] TJ ET BT 26.250 448.887 Td /F1 9.8 Tf [(A genetic test result allows an individual to make decisions relating to family planning. It can also be useful to inform treatment )] TJ ET BT 26.250 436.982 Td /F1 9.8 Tf [(planning. Patients with a )] TJ ET BT 134.641 436.982 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 160.644 436.982 Td /F1 9.8 Tf [( mutation may be offered the opportunity to enrol into clinical trials. )] TJ ET BT 450.024 436.982 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 478.738 436.982 Td /F1 9.8 Tf [(encodes a )] TJ ET BT 26.250 425.077 Td /F1 9.8 Tf [(deubiquitinating enzyme that negatively regulates the nuclear factor-kappa beta pathway. A clinical trial using topical salicylic )] TJ ET BT 26.250 413.172 Td /F1 9.8 Tf [(acid was not promising)] TJ ET 0.267 0.267 0.267 rg BT 125.407 414.680 Td /F6 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 130.226 413.172 Td /F1 9.8 Tf [( . More recently gene expression profiling of tumours in patients with germline )] TJ ET BT 467.274 413.172 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 493.277 413.172 Td /F1 9.8 Tf [( mutations have )] TJ ET BT 26.250 401.268 Td /F1 9.8 Tf [(shown dysregulated tropomyosin kinase \(TRK\) signalling, and treatment with lestaurtinib, a TRK inhibitor reduced growth of )] TJ ET BT 26.250 389.363 Td /F1 9.8 Tf [(cells established from )] TJ ET BT 122.697 389.363 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 151.411 389.363 Td /F1 9.8 Tf [(mutant tumours in vitro)] TJ ET 0.267 0.267 0.267 rg BT 250.568 390.870 Td /F6 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 255.387 389.363 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 352.760 Td /F6 12.0 Tf [(Published reviews, recommendations and guidelines)] TJ ET BT 26.250 332.806 Td /F1 9.8 Tf [(Systematic evidence reviews: None identified)] TJ ET BT 26.250 313.401 Td /F1 9.8 Tf [(Recommendations by independent groups: UK GTN Gene dossier)] TJ ET BT 26.250 293.997 Td /F1 9.8 Tf [(Guidelines by professional groups: None identified)] TJ ET BT 26.250 257.394 Td /F6 12.0 Tf [(Evidence Overview)] TJ ET BT 26.250 237.440 Td /F6 9.8 Tf [(Analytic validity:)] TJ ET BT 26.250 218.035 Td /F1 9.8 Tf [(The testing methodology involves bi-directional fluorescent DNA sequencing of all coding exons of CYLD \(exons 4-20, exonic )] TJ ET BT 26.250 206.130 Td /F1 9.8 Tf [(sequence plus at least 10bp at the 5 and 3 of each intron\). This method would be expected to detect >99% of mutations )] TJ ET BT 26.250 194.226 Td /F1 9.8 Tf [(within the coding region/splice sites, excluding duplications and large deletions. Large deletions have been reported to affect a )] TJ ET BT 26.250 182.321 Td /F1 9.8 Tf [(minority of patients that are mutation negative following Sanger sequencing.)] TJ ET 0.267 0.267 0.267 rg BT 353.577 183.828 Td /F6 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 358.396 182.321 Td /F1 9.8 Tf [( cDNA testing is also carried out where )] TJ ET BT 26.250 170.416 Td /F1 9.8 Tf [(appropriate. The generic techniques are well established in the CPA-accredited Northern Genetics Service laboratory.)] TJ ET BT 26.250 151.011 Td /F6 9.8 Tf [(Validation:)] TJ ET BT 26.250 131.607 Td /F1 9.8 Tf [(The testing protocol was validated in confirming the findings of the research study described below.)] TJ ET BT 26.250 112.202 Td /F6 9.8 Tf [(Analytic sensitivity:)] TJ ET BT 26.250 92.797 Td /F1 9.8 Tf [(The analytic sensitivity and specificity are close to 100% for the techniques used.)] TJ ET BT 26.250 73.392 Td /F6 9.8 Tf [(Clinical validity:)] TJ ET BT 26.250 53.988 Td /F1 9.8 Tf [(A study investigating the mutational spectrum of )] TJ ET BT 235.972 53.988 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 264.686 53.988 Td /F1 9.8 Tf [(and genotype-phenotype correlation)] TJ ET 0.267 0.267 0.267 rg BT 420.774 55.495 Td /F6 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 425.593 53.988 Td /F1 9.8 Tf [( tested a total of 47 samples from )] TJ ET BT 26.250 42.083 Td /F1 9.8 Tf [(25 families exhibiting BSS, MFT or FC phenotypes. Of these families, 13 had clinical features of BSS, three of FC and nine of )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(3)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Evidence on Genomic Tests)] TJ ET Q endstream endobj 95 0 obj << /Type /Annot /Subtype /Link /A 96 0 R /Border [0 0 0] /H /I /Rect [ 155.2328 744.3722 160.0514 753.1905 ] >> endobj 96 0 obj << /Type /Action >> endobj 97 0 obj << /Type /Annot /Subtype /Link /A 98 0 R /Border [0 0 0] /H /I /Rect [ 229.9860 720.5627 234.8047 729.3810 ] >> endobj 98 0 obj << /Type /Action >> endobj 99 0 obj << /Type /Annot /Subtype /Link /A 100 0 R /Border [0 0 0] /H /I /Rect [ 262.5023 677.3484 267.3209 686.1667 ] >> endobj 100 0 obj << /Type /Action >> endobj 101 0 obj << /Type /Annot /Subtype /Link /A 102 0 R /Border [0 0 0] /H /I /Rect [ 237.6008 665.4437 242.4194 674.2620 ] >> endobj 102 0 obj << /Type /Action >> endobj 103 0 obj << /Type /Annot /Subtype /Link /A 104 0 R /Border [0 0 0] /H /I /Rect [ 125.4075 413.8779 130.2262 422.6963 ] >> endobj 104 0 obj << /Type /Action >> endobj 105 0 obj << /Type /Annot /Subtype /Link /A 106 0 R /Border [0 0 0] /H /I /Rect [ 250.5683 390.0684 255.3869 398.8868 ] >> endobj 106 0 obj << /Type /Action >> endobj 107 0 obj << /Type /Annot /Subtype /Link /A 108 0 R /Border [0 0 0] /H /I /Rect [ 353.5770 183.0264 358.3957 191.8447 ] >> endobj 108 0 obj << /Type /Action >> endobj 109 0 obj << /Type /Annot /Subtype /Link /A 110 0 R /Border [0 0 0] /H /I /Rect [ 420.7740 54.6932 425.5927 63.5115 ] >> endobj 110 0 obj << /Type /Action >> endobj 111 0 obj << /Type /Annot /Subtype /Link /A 112 0 R /Border [0 0 0] /H /I /Rect [ 155.2328 744.3722 160.0514 753.1905 ] >> endobj 112 0 obj << /Type /Action >> endobj 113 0 obj << /Type /Annot /Subtype /Link /A 114 0 R /Border [0 0 0] /H /I /Rect [ 229.9860 720.5627 234.8047 729.3810 ] >> endobj 114 0 obj << /Type /Action >> endobj 115 0 obj << /Type /Annot /Subtype /Link /A 116 0 R /Border [0 0 0] /H /I /Rect [ 262.5023 677.3484 267.3209 686.1667 ] >> endobj 116 0 obj << /Type /Action >> endobj 117 0 obj << /Type /Annot /Subtype /Link /A 118 0 R /Border [0 0 0] /H /I /Rect [ 237.6008 665.4437 242.4194 674.2620 ] >> endobj 118 0 obj << /Type /Action >> endobj 119 0 obj << /Type /Annot /Subtype /Link /A 120 0 R /Border [0 0 0] /H /I /Rect [ 125.4075 413.8779 130.2262 422.6963 ] >> endobj 120 0 obj << /Type /Action >> endobj 121 0 obj << /Type /Annot /Subtype /Link /A 122 0 R /Border [0 0 0] /H /I /Rect [ 250.5683 390.0684 255.3869 398.8868 ] >> endobj 122 0 obj << /Type /Action >> endobj 123 0 obj << /Type /Annot /Subtype /Link /A 124 0 R /Border [0 0 0] /H /I /Rect [ 353.5770 183.0264 358.3957 191.8447 ] >> endobj 124 0 obj << /Type /Action >> endobj 125 0 obj << /Type /Annot /Subtype /Link /A 126 0 R /Border [0 0 0] /H /I /Rect [ 420.7740 54.6932 425.5927 63.5115 ] >> endobj 126 0 obj << /Type /Action >> endobj 127 0 obj << /Type /Annot /Subtype /Link /A 128 0 R /Border [0 0 0] /H /I /Rect [ 155.2328 744.3722 160.0514 753.1905 ] >> endobj 128 0 obj << /Type /Action >> endobj 129 0 obj << /Type /Annot /Subtype /Link /A 130 0 R /Border [0 0 0] /H /I /Rect [ 229.9860 720.5627 234.8047 729.3810 ] >> endobj 130 0 obj << /Type /Action >> endobj 131 0 obj << /Type /Annot /Subtype /Link /A 132 0 R /Border [0 0 0] /H /I /Rect [ 262.5023 677.3484 267.3209 686.1667 ] >> endobj 132 0 obj << /Type /Action >> endobj 133 0 obj << /Type /Annot /Subtype /Link /A 134 0 R /Border [0 0 0] /H /I /Rect [ 237.6008 665.4437 242.4194 674.2620 ] >> endobj 134 0 obj << /Type /Action >> endobj 135 0 obj << /Type /Annot /Subtype /Link /A 136 0 R /Border [0 0 0] /H /I /Rect [ 125.4075 413.8779 130.2262 422.6963 ] >> endobj 136 0 obj << /Type /Action >> endobj 137 0 obj << /Type /Annot /Subtype /Link /A 138 0 R /Border [0 0 0] /H /I /Rect [ 250.5683 390.0684 255.3869 398.8868 ] >> endobj 138 0 obj << /Type /Action >> endobj 139 0 obj << /Type /Annot /Subtype /Link /A 140 0 R /Border [0 0 0] /H /I /Rect [ 353.5770 183.0264 358.3957 191.8447 ] >> endobj 140 0 obj << /Type /Action >> endobj 141 0 obj << /Type /Annot /Subtype /Link /A 142 0 R /Border [0 0 0] /H /I /Rect [ 420.7740 54.6932 425.5927 63.5115 ] >> endobj 142 0 obj << /Type /Action >> endobj 143 0 obj << /Type /Page /Parent 3 0 R /Annots [ 145 0 R 147 0 R 149 0 R ] /Contents 144 0 R >> endobj 144 0 obj << /Length 19703 >> stream 0.271 0.267 0.267 rg q 15.000 67.916 577.500 709.084 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(MFT. Mutations in )] TJ ET BT 106.980 767.476 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 132.983 767.476 Td /F1 9.8 Tf [( were present in 11/13 with BSS \(85%\), 3/3 with FC \(100%\) and 4/9 families with MFT \(44%\). This )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(gave an overall mutation detection rate of 18/25 \(72%\) in these families.)] TJ ET BT 26.250 718.969 Td /F6 12.0 Tf [(Clinical Utility)] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(The genetic predisposition to these tumours is rare. Although cylindromas carry a significant burden of disease, they are usually )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(not life threatening, which may explain why there are few studies looking at the benefits of genetic testing in affected or at risk )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(individuals. Anecdotal evidence is described in one study of 26 affected patients.)] TJ ET 0.267 0.267 0.267 rg BT 373.642 676.712 Td /F6 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 378.461 675.205 Td /F1 9.8 Tf [( In this study, issues relating to genetic )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(counselling which are relevant to those undergoing genetic testing for )] TJ ET BT 328.110 663.300 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 354.113 663.300 Td /F1 9.8 Tf [( mutations are explored. When a pathogenic )] TJ ET BT 26.250 651.396 Td /F1 9.8 Tf [(mutation in )] TJ ET BT 76.648 651.396 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 105.362 651.396 Td /F1 9.8 Tf [(is identified in a patient who meets the criteria for testing, they have the advantage of knowing their diagnosis )] TJ ET BT 26.250 639.491 Td /F1 9.8 Tf [(is confirmed, and can use the information for their benefit. Patients who present with multiple skin appendage tumours but are )] TJ ET BT 26.250 627.586 Td /F1 9.8 Tf [(not known to have a family history may not have considered that their tumours could represent an underlying genetic cause. )] TJ ET BT 26.250 615.681 Td /F1 9.8 Tf [(The knowledge that this is so can help them anticipate the fact that further tumours may develop and prepare for necessary )] TJ ET BT 26.250 603.777 Td /F1 9.8 Tf [(treatment. Testing is also facilitated for family members should they develop tumours. Individuals with a family history but no )] TJ ET BT 26.250 591.872 Td /F1 9.8 Tf [(tumours themselves are aware they are at 50% risk of having a )] TJ ET BT 301.531 591.872 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 330.245 591.872 Td /F1 9.8 Tf [(mutation. Having the test on a presymptomatic basis can )] TJ ET BT 26.250 579.967 Td /F1 9.8 Tf [(reassure patients if they receive a negative result, and allow them to make decisions about the future if they know the result is )] TJ ET BT 26.250 568.062 Td /F1 9.8 Tf [(positive. Although prenatal diagnostic testing is not offered for this condition, some patients with a )] TJ ET BT 448.961 568.062 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 474.964 568.062 Td /F1 9.8 Tf [( mutation may choose )] TJ ET BT 26.250 556.158 Td /F1 9.8 Tf [(to use the information to influence family planning decisions. Patients with a mutation may choose to be entered into appropriate )] TJ ET BT 26.250 544.253 Td /F1 9.8 Tf [(clinical trials when the opportunity arises.)] TJ ET BT 26.250 507.650 Td /F6 12.0 Tf [(Links)] TJ ET BT 26.250 487.696 Td /F1 9.8 Tf [(UKGTN Homepage: https://ukgtn.nhs.uk/)] TJ ET BT 26.250 468.291 Td /F1 9.8 Tf [(UKGTN Test Dossier: https://ukgtn.nhs.uk/find-a-test/gene-dossiers/)] TJ ET BT 26.250 448.887 Td /F1 9.8 Tf [(UKGTN Testing Criteria: https://ukgtn.nhs.uk/resources/testing-criteria/)] TJ ET BT 26.250 412.284 Td /F6 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 392.330 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 355.727 Td /F6 12.0 Tf [(References)] TJ ET BT 26.250 328.273 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 328.273 Td /F1 9.8 Tf [(Young AL, Kellermayer R, Szigeti R et al. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple )] TJ ET BT 26.250 316.368 Td /F1 9.8 Tf [(familial trichoepithelioma syndromes. Clin Genet 2006;70:246-249.)] TJ ET BT 26.250 296.964 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 296.964 Td /F1 9.8 Tf [(Rajan N, Langtry JAA, Ashworth A et al. Tumor mapping in two large multigeneration families with CYLD mutations: )] TJ ET BT 26.250 285.059 Td /F1 9.8 Tf [(Implications for patient management and tumor induction. Arch Dermatol 2009;145\(11\):1277-1284.)] TJ ET BT 26.250 265.654 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 265.654 Td /F1 9.8 Tf [(Freedman AM, Woods JE. Total scalp excision and auricular resurfacing for dermal cylindroma \(turban tumour\). Ann Plast )] TJ ET BT 26.250 253.749 Td /F1 9.8 Tf [(Surg 1989;22:50-57.)] TJ ET BT 26.250 234.345 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 234.345 Td /F1 9.8 Tf [(Rajan N, Trainer AH, Burn J et al. Familial Cylindromatosis and Brooke-Spiegler Syndrome: A review of current therapeutic )] TJ ET BT 26.250 222.440 Td /F1 9.8 Tf [(approaches and the surgical challenges posed by two affected families. Dermatol Surg 2009;35:845-852.)] TJ ET BT 26.250 203.035 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 203.035 Td /F1 9.8 Tf [(Oosterkamp HM, Neering H, Nijman SM, et al. An evaluation of the efficacy of topical application of salicylic acid for the )] TJ ET BT 26.250 191.130 Td /F1 9.8 Tf [(treatment of familial cylindromatosis. Br J Dermatol 2006;155:182-185.)] TJ ET BT 26.250 171.726 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 171.726 Td /F1 9.8 Tf [(Rajan N, Elliot R, Clewes O, et al. Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours. Oncogene )] TJ ET BT 26.250 159.821 Td /F1 9.8 Tf [(2011;30\(41\):4243-4260.)] TJ ET BT 26.250 140.416 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 140.416 Td /F1 9.8 Tf [(Vanecek T, Halbhuber Z, Kacerovska D, Martinek P, Sedivcova M, Carr RA, Slouka D, Michal M, Kazakov DV. Large )] TJ ET BT 26.250 128.511 Td /F1 9.8 Tf [(germline deletions of the CYLD gene in patients with Brooke-Spiegler syndrome and multiple familial trichoepithelioma. Am J )] TJ ET BT 26.250 116.607 Td /F1 9.8 Tf [(Dermatopathol. 2014 Nov;36\(11\):868-74. PubMed PMID:25347032.)] TJ ET BT 26.250 97.202 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 97.202 Td /F1 9.8 Tf [(Sagar S, Chernoff KA, Lodha S, et al. CYLD mutations in familial skin appendage tumours. J Med Genet 2008;45\(5\):298-)] TJ ET BT 26.250 85.297 Td /F1 9.8 Tf [(302.)] TJ ET Q q 15.000 67.916 577.500 709.084 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(MFT. Mutations in )] TJ ET BT 106.980 767.476 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 132.983 767.476 Td /F1 9.8 Tf [( were present in 11/13 with BSS \(85%\), 3/3 with FC \(100%\) and 4/9 families with MFT \(44%\). This )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(gave an overall mutation detection rate of 18/25 \(72%\) in these families.)] TJ ET BT 26.250 718.969 Td /F6 12.0 Tf [(Clinical Utility)] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(The genetic predisposition to these tumours is rare. Although cylindromas carry a significant burden of disease, they are usually )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(not life threatening, which may explain why there are few studies looking at the benefits of genetic testing in affected or at risk )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(individuals. Anecdotal evidence is described in one study of 26 affected patients.)] TJ ET 0.267 0.267 0.267 rg BT 373.642 676.712 Td /F6 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 378.461 675.205 Td /F1 9.8 Tf [( In this study, issues relating to genetic )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(counselling which are relevant to those undergoing genetic testing for )] TJ ET BT 328.110 663.300 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 354.113 663.300 Td /F1 9.8 Tf [( mutations are explored. When a pathogenic )] TJ ET BT 26.250 651.396 Td /F1 9.8 Tf [(mutation in )] TJ ET BT 76.648 651.396 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 105.362 651.396 Td /F1 9.8 Tf [(is identified in a patient who meets the criteria for testing, they have the advantage of knowing their diagnosis )] TJ ET BT 26.250 639.491 Td /F1 9.8 Tf [(is confirmed, and can use the information for their benefit. Patients who present with multiple skin appendage tumours but are )] TJ ET BT 26.250 627.586 Td /F1 9.8 Tf [(not known to have a family history may not have considered that their tumours could represent an underlying genetic cause. )] TJ ET BT 26.250 615.681 Td /F1 9.8 Tf [(The knowledge that this is so can help them anticipate the fact that further tumours may develop and prepare for necessary )] TJ ET BT 26.250 603.777 Td /F1 9.8 Tf [(treatment. Testing is also facilitated for family members should they develop tumours. Individuals with a family history but no )] TJ ET BT 26.250 591.872 Td /F1 9.8 Tf [(tumours themselves are aware they are at 50% risk of having a )] TJ ET BT 301.531 591.872 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 330.245 591.872 Td /F1 9.8 Tf [(mutation. Having the test on a presymptomatic basis can )] TJ ET BT 26.250 579.967 Td /F1 9.8 Tf [(reassure patients if they receive a negative result, and allow them to make decisions about the future if they know the result is )] TJ ET BT 26.250 568.062 Td /F1 9.8 Tf [(positive. Although prenatal diagnostic testing is not offered for this condition, some patients with a )] TJ ET BT 448.961 568.062 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 474.964 568.062 Td /F1 9.8 Tf [( mutation may choose )] TJ ET BT 26.250 556.158 Td /F1 9.8 Tf [(to use the information to influence family planning decisions. Patients with a mutation may choose to be entered into appropriate )] TJ ET BT 26.250 544.253 Td /F1 9.8 Tf [(clinical trials when the opportunity arises.)] TJ ET BT 26.250 507.650 Td /F6 12.0 Tf [(Links)] TJ ET BT 26.250 487.696 Td /F1 9.8 Tf [(UKGTN Homepage: https://ukgtn.nhs.uk/)] TJ ET BT 26.250 468.291 Td /F1 9.8 Tf [(UKGTN Test Dossier: https://ukgtn.nhs.uk/find-a-test/gene-dossiers/)] TJ ET BT 26.250 448.887 Td /F1 9.8 Tf [(UKGTN Testing Criteria: https://ukgtn.nhs.uk/resources/testing-criteria/)] TJ ET BT 26.250 412.284 Td /F6 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 392.330 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 355.727 Td /F6 12.0 Tf [(References)] TJ ET BT 26.250 328.273 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 328.273 Td /F1 9.8 Tf [(Young AL, Kellermayer R, Szigeti R et al. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple )] TJ ET BT 26.250 316.368 Td /F1 9.8 Tf [(familial trichoepithelioma syndromes. Clin Genet 2006;70:246-249.)] TJ ET BT 26.250 296.964 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 296.964 Td /F1 9.8 Tf [(Rajan N, Langtry JAA, Ashworth A et al. Tumor mapping in two large multigeneration families with CYLD mutations: )] TJ ET BT 26.250 285.059 Td /F1 9.8 Tf [(Implications for patient management and tumor induction. Arch Dermatol 2009;145\(11\):1277-1284.)] TJ ET BT 26.250 265.654 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 265.654 Td /F1 9.8 Tf [(Freedman AM, Woods JE. Total scalp excision and auricular resurfacing for dermal cylindroma \(turban tumour\). Ann Plast )] TJ ET BT 26.250 253.749 Td /F1 9.8 Tf [(Surg 1989;22:50-57.)] TJ ET BT 26.250 234.345 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 234.345 Td /F1 9.8 Tf [(Rajan N, Trainer AH, Burn J et al. Familial Cylindromatosis and Brooke-Spiegler Syndrome: A review of current therapeutic )] TJ ET BT 26.250 222.440 Td /F1 9.8 Tf [(approaches and the surgical challenges posed by two affected families. Dermatol Surg 2009;35:845-852.)] TJ ET BT 26.250 203.035 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 203.035 Td /F1 9.8 Tf [(Oosterkamp HM, Neering H, Nijman SM, et al. An evaluation of the efficacy of topical application of salicylic acid for the )] TJ ET BT 26.250 191.130 Td /F1 9.8 Tf [(treatment of familial cylindromatosis. Br J Dermatol 2006;155:182-185.)] TJ ET BT 26.250 171.726 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 171.726 Td /F1 9.8 Tf [(Rajan N, Elliot R, Clewes O, et al. Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours. Oncogene )] TJ ET BT 26.250 159.821 Td /F1 9.8 Tf [(2011;30\(41\):4243-4260.)] TJ ET BT 26.250 140.416 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 140.416 Td /F1 9.8 Tf [(Vanecek T, Halbhuber Z, Kacerovska D, Martinek P, Sedivcova M, Carr RA, Slouka D, Michal M, Kazakov DV. Large )] TJ ET BT 26.250 128.511 Td /F1 9.8 Tf [(germline deletions of the CYLD gene in patients with Brooke-Spiegler syndrome and multiple familial trichoepithelioma. Am J )] TJ ET BT 26.250 116.607 Td /F1 9.8 Tf [(Dermatopathol. 2014 Nov;36\(11\):868-74. PubMed PMID:25347032.)] TJ ET BT 26.250 97.202 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 97.202 Td /F1 9.8 Tf [(Sagar S, Chernoff KA, Lodha S, et al. CYLD mutations in familial skin appendage tumours. J Med Genet 2008;45\(5\):298-)] TJ ET BT 26.250 85.297 Td /F1 9.8 Tf [(302.)] TJ ET Q q 15.000 67.916 577.500 709.084 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(MFT. Mutations in )] TJ ET BT 106.980 767.476 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 132.983 767.476 Td /F1 9.8 Tf [( were present in 11/13 with BSS \(85%\), 3/3 with FC \(100%\) and 4/9 families with MFT \(44%\). This )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(gave an overall mutation detection rate of 18/25 \(72%\) in these families.)] TJ ET BT 26.250 718.969 Td /F6 12.0 Tf [(Clinical Utility)] TJ ET BT 26.250 699.015 Td /F1 9.8 Tf [(The genetic predisposition to these tumours is rare. Although cylindromas carry a significant burden of disease, they are usually )] TJ ET BT 26.250 687.110 Td /F1 9.8 Tf [(not life threatening, which may explain why there are few studies looking at the benefits of genetic testing in affected or at risk )] TJ ET BT 26.250 675.205 Td /F1 9.8 Tf [(individuals. Anecdotal evidence is described in one study of 26 affected patients.)] TJ ET 0.267 0.267 0.267 rg BT 373.642 676.712 Td /F6 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 378.461 675.205 Td /F1 9.8 Tf [( In this study, issues relating to genetic )] TJ ET BT 26.250 663.300 Td /F1 9.8 Tf [(counselling which are relevant to those undergoing genetic testing for )] TJ ET BT 328.110 663.300 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 354.113 663.300 Td /F1 9.8 Tf [( mutations are explored. When a pathogenic )] TJ ET BT 26.250 651.396 Td /F1 9.8 Tf [(mutation in )] TJ ET BT 76.648 651.396 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 105.362 651.396 Td /F1 9.8 Tf [(is identified in a patient who meets the criteria for testing, they have the advantage of knowing their diagnosis )] TJ ET BT 26.250 639.491 Td /F1 9.8 Tf [(is confirmed, and can use the information for their benefit. Patients who present with multiple skin appendage tumours but are )] TJ ET BT 26.250 627.586 Td /F1 9.8 Tf [(not known to have a family history may not have considered that their tumours could represent an underlying genetic cause. )] TJ ET BT 26.250 615.681 Td /F1 9.8 Tf [(The knowledge that this is so can help them anticipate the fact that further tumours may develop and prepare for necessary )] TJ ET BT 26.250 603.777 Td /F1 9.8 Tf [(treatment. Testing is also facilitated for family members should they develop tumours. Individuals with a family history but no )] TJ ET BT 26.250 591.872 Td /F1 9.8 Tf [(tumours themselves are aware they are at 50% risk of having a )] TJ ET BT 301.531 591.872 Td /F5 9.8 Tf [(CYLD )] TJ ET BT 330.245 591.872 Td /F1 9.8 Tf [(mutation. Having the test on a presymptomatic basis can )] TJ ET BT 26.250 579.967 Td /F1 9.8 Tf [(reassure patients if they receive a negative result, and allow them to make decisions about the future if they know the result is )] TJ ET BT 26.250 568.062 Td /F1 9.8 Tf [(positive. Although prenatal diagnostic testing is not offered for this condition, some patients with a )] TJ ET BT 448.961 568.062 Td /F5 9.8 Tf [(CYLD)] TJ ET BT 474.964 568.062 Td /F1 9.8 Tf [( mutation may choose )] TJ ET BT 26.250 556.158 Td /F1 9.8 Tf [(to use the information to influence family planning decisions. Patients with a mutation may choose to be entered into appropriate )] TJ ET BT 26.250 544.253 Td /F1 9.8 Tf [(clinical trials when the opportunity arises.)] TJ ET BT 26.250 507.650 Td /F6 12.0 Tf [(Links)] TJ ET BT 26.250 487.696 Td /F1 9.8 Tf [(UKGTN Homepage: https://ukgtn.nhs.uk/)] TJ ET BT 26.250 468.291 Td /F1 9.8 Tf [(UKGTN Test Dossier: https://ukgtn.nhs.uk/find-a-test/gene-dossiers/)] TJ ET BT 26.250 448.887 Td /F1 9.8 Tf [(UKGTN Testing Criteria: https://ukgtn.nhs.uk/resources/testing-criteria/)] TJ ET BT 26.250 412.284 Td /F6 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 392.330 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 355.727 Td /F6 12.0 Tf [(References)] TJ ET BT 26.250 328.273 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 328.273 Td /F1 9.8 Tf [(Young AL, Kellermayer R, Szigeti R et al. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple )] TJ ET BT 26.250 316.368 Td /F1 9.8 Tf [(familial trichoepithelioma syndromes. Clin Genet 2006;70:246-249.)] TJ ET BT 26.250 296.964 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 296.964 Td /F1 9.8 Tf [(Rajan N, Langtry JAA, Ashworth A et al. Tumor mapping in two large multigeneration families with CYLD mutations: )] TJ ET BT 26.250 285.059 Td /F1 9.8 Tf [(Implications for patient management and tumor induction. Arch Dermatol 2009;145\(11\):1277-1284.)] TJ ET BT 26.250 265.654 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 265.654 Td /F1 9.8 Tf [(Freedman AM, Woods JE. Total scalp excision and auricular resurfacing for dermal cylindroma \(turban tumour\). Ann Plast )] TJ ET BT 26.250 253.749 Td /F1 9.8 Tf [(Surg 1989;22:50-57.)] TJ ET BT 26.250 234.345 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 234.345 Td /F1 9.8 Tf [(Rajan N, Trainer AH, Burn J et al. Familial Cylindromatosis and Brooke-Spiegler Syndrome: A review of current therapeutic )] TJ ET BT 26.250 222.440 Td /F1 9.8 Tf [(approaches and the surgical challenges posed by two affected families. Dermatol Surg 2009;35:845-852.)] TJ ET BT 26.250 203.035 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 203.035 Td /F1 9.8 Tf [(Oosterkamp HM, Neering H, Nijman SM, et al. An evaluation of the efficacy of topical application of salicylic acid for the )] TJ ET BT 26.250 191.130 Td /F1 9.8 Tf [(treatment of familial cylindromatosis. Br J Dermatol 2006;155:182-185.)] TJ ET BT 26.250 171.726 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 171.726 Td /F1 9.8 Tf [(Rajan N, Elliot R, Clewes O, et al. Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours. Oncogene )] TJ ET BT 26.250 159.821 Td /F1 9.8 Tf [(2011;30\(41\):4243-4260.)] TJ ET BT 26.250 140.416 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 140.416 Td /F1 9.8 Tf [(Vanecek T, Halbhuber Z, Kacerovska D, Martinek P, Sedivcova M, Carr RA, Slouka D, Michal M, Kazakov DV. Large )] TJ ET BT 26.250 128.511 Td /F1 9.8 Tf [(germline deletions of the CYLD gene in patients with Brooke-Spiegler syndrome and multiple familial trichoepithelioma. Am J )] TJ ET BT 26.250 116.607 Td /F1 9.8 Tf [(Dermatopathol. 2014 Nov;36\(11\):868-74. PubMed PMID:25347032.)] TJ ET BT 26.250 97.202 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 97.202 Td /F1 9.8 Tf [(Sagar S, Chernoff KA, Lodha S, et al. CYLD mutations in familial skin appendage tumours. J Med Genet 2008;45\(5\):298-)] TJ ET BT 26.250 85.297 Td /F1 9.8 Tf [(302.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(4)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Evidence on Genomic Tests)] TJ ET Q endstream endobj 145 0 obj << /Type /Annot /Subtype /Link /A 146 0 R /Border [0 0 0] /H /I /Rect [ 373.6425 675.9107 378.4612 684.7290 ] >> endobj 146 0 obj << /Type /Action >> endobj 147 0 obj << /Type /Annot /Subtype /Link /A 148 0 R /Border [0 0 0] /H /I /Rect [ 373.6425 675.9107 378.4612 684.7290 ] >> endobj 148 0 obj << /Type /Action >> endobj 149 0 obj << /Type /Annot /Subtype /Link /A 150 0 R /Border [0 0 0] /H /I /Rect [ 373.6425 675.9107 378.4612 684.7290 ] >> endobj 150 0 obj << /Type /Action >> endobj xref 0 151 0000000000 65535 f 0000000008 00000 n 0000000073 00000 n 0000000119 00000 n 0000000420 00000 n 0000000457 00000 n 0000000738 00000 n 0000001023 00000 n 0000015945 00000 n 0000016052 00000 n 0000016166 00000 n 0000016275 00000 n 0000016386 00000 n 0000016502 00000 n 0000016615 00000 n 0000017003 00000 n 0000021832 00000 n 0000021959 00000 n 0000022173 00000 n 0000022299 00000 n 0000022513 00000 n 0000022640 00000 n 0000022854 00000 n 0000022981 00000 n 0000023099 00000 n 0000023225 00000 n 0000023327 00000 n 0000023454 00000 n 0000023577 00000 n 0000023705 00000 n 0000023833 00000 n 0000023961 00000 n 0000024078 00000 n 0000024206 00000 n 0000024242 00000 n 0000024368 00000 n 0000024486 00000 n 0000058214 00000 n 0000058341 00000 n 0000058555 00000 n 0000058681 00000 n 0000058895 00000 n 0000059022 00000 n 0000059236 00000 n 0000059363 00000 n 0000059481 00000 n 0000059607 00000 n 0000059709 00000 n 0000059836 00000 n 0000059959 00000 n 0000060087 00000 n 0000060215 00000 n 0000060343 00000 n 0000060460 00000 n 0000060588 00000 n 0000060624 00000 n 0000060750 00000 n 0000060868 00000 n 0000060995 00000 n 0000061209 00000 n 0000061335 00000 n 0000061549 00000 n 0000061676 00000 n 0000061890 00000 n 0000062017 00000 n 0000062135 00000 n 0000062261 00000 n 0000062363 00000 n 0000062490 00000 n 0000062613 00000 n 0000062741 00000 n 0000062869 00000 n 0000062997 00000 n 0000063114 00000 n 0000063242 00000 n 0000063278 00000 n 0000063404 00000 n 0000063522 00000 n 0000063641 00000 n 0000073351 00000 n 0000073478 00000 n 0000073596 00000 n 0000096338 00000 n 0000096465 00000 n 0000096582 00000 n 0000131463 00000 n 0000131590 00000 n 0000131708 00000 n 0000131835 00000 n 0000131952 00000 n 0000132079 00000 n 0000132197 00000 n 0000132324 00000 n 0000132441 00000 n 0000132707 00000 n 0000156919 00000 n 0000157047 00000 n 0000157083 00000 n 0000157211 00000 n 0000157247 00000 n 0000157376 00000 n 0000157413 00000 n 0000157543 00000 n 0000157580 00000 n 0000157710 00000 n 0000157747 00000 n 0000157877 00000 n 0000157914 00000 n 0000158044 00000 n 0000158081 00000 n 0000158209 00000 n 0000158246 00000 n 0000158376 00000 n 0000158413 00000 n 0000158543 00000 n 0000158580 00000 n 0000158710 00000 n 0000158747 00000 n 0000158877 00000 n 0000158914 00000 n 0000159044 00000 n 0000159081 00000 n 0000159211 00000 n 0000159248 00000 n 0000159378 00000 n 0000159415 00000 n 0000159543 00000 n 0000159580 00000 n 0000159710 00000 n 0000159747 00000 n 0000159877 00000 n 0000159914 00000 n 0000160044 00000 n 0000160081 00000 n 0000160211 00000 n 0000160248 00000 n 0000160378 00000 n 0000160415 00000 n 0000160545 00000 n 0000160582 00000 n 0000160712 00000 n 0000160749 00000 n 0000160877 00000 n 0000160914 00000 n 0000161017 00000 n 0000180775 00000 n 0000180905 00000 n 0000180942 00000 n 0000181072 00000 n 0000181109 00000 n 0000181239 00000 n trailer << /Size 151 /Root 1 0 R /Info 5 0 R >> startxref 181276 %%EOF