Photodermatology, Photoimmunology & Photomedicine
LETTER TO THE EDITOR
Photosensitive form of trichothiodystrophy associated with a novel mutation in the XPD gene € rner3, Knut Brockmann4, Birka Brauns1,2, Steffen Schubert1, Janin Lehmann1, Petra Laspe1, Andrea Ko 1,5 1,2 € n & Steffen Emmert Michael P. Scho
1
Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University, € ttingen, Germany. Go 2 Clinic for Dermatology and Venereology, University Medical Center Rostock, Rostock, Germany. 3 DWI – Leibniz Institute for Interactive Materials, Aachen, Germany. 4 Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center, Georg August University, € ttingen, Germany. Go 5 Lower Saxony Institute of Occupational Dermatology, € ttingen and University of University Medical Center Go € ck, Osnabru € ck, Germany. Osnabru
Correspondence: Steffen Emmert, M.D., Clinic for Dermatology and Venereology, University Medical Center Rostock, D-18057 Rostock, Germany. Tel: +49 (0)381 4949701 Fax: 49 (0)381 4949702 e-mail: [email protected]
Accepted for publication: 27 October 2015
Funding sources: €chsische This work was supported by a grant from the Niedersa Krebsgesellschaft e.V. (to SE and SS).
Conflicts of interest: None.
To the Editor, The term ‘trichothiodystrophy’ (TTD) was introduced by Price et al. (1) in 1980 to describe a group of rare autosomal recessive disorders characterized by sulfur-deficient brittle hair and other neuroectodermal symptoms. An eight-week-old boy was referred to our clinic with dry, scaly skin on the trunk and dorsal extremities 110
sparing the flexures (Fig. 1a,b). In the second year of his life, however, the patient additionally exhibited short, brittle hair (Fig. 1c) and nails, nail dystrophy, photosensitivity, mild delay of motor and speech development, and marked ataxia. At age 2 years, weight, length, and head circumference were within normal ranges. There were no ocular defects. He also suffered from frequent febrile infections of the upper respiratory system. Analysis of the patient’s hair by light microscopy revealed transverse fractures (trichoschisis) (Fig. 1d). Alternating dark and light bands of his hair shafts (‘tiger-tail’ banding) were discovered using polarizing microscopy (Fig. 1e,f). Subsequently, amino acid analysis of hydrolyzed hairs showed a markedly reduced cystine content of 3.5 mol/100 mol compared to 9.4 mol/100 mol in the control hair of a healthy boy. This characteristic constellation led to the diagnosis of trichothiodystrophy (TTD). Magnetic resonance imaging of the brain revealed mild diffuse T2-hyperintensity of supratentorial white matter consistent with dysmyelination, as described previously in TTD. We established a fibroblast cell line (TTD5GO) from a skin punch biopsy. After irradiation with 30 J/m2 UVC, the cells showed a reduced relative post-UV cell survival (% of nonirradiated cells) (2, 3) rate of only 61.4 2.2% compared to >75% of normal fibroblasts (Fig. 2a,b). As most photosensitive forms of TTD are predominantly caused by defects in the xeroderma pigmentosum group D gene (XPD/ERCC2) rather than by mutations in XPB/ ERCC3 or TTDA (4), we performed XPD gene sequencing. Indeed, the patient was compound heterozygous for two mutations in XPD: c.2164C>T (p.R722W; from father), described at least in 13 patients and known TTD-causing (2, 3) and a novel TTD-associated c.2174C>T mutation (p.A725V; from mother). Interestingly, another amino acid exchange at the same position (p.A725P) has been previously identified as TTD-causing (5) in another patient. Re-introducing wild-type XPD cDNA into TTD5GO cells increased their repair capacity threefold as assessed by host-cell reactivation (3) indicating complementation by XPD (Fig. 2c). ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd doi:10.1111/phpp.12225
Letter to the Editor
(a)
(d)
(b)
(e)
(c)
(f)
Fig. 1. Clinical features of trichothiodystrophy in a young boy showing dry, scaly skin on the trunk and dorsal extremities sparing the flexures at eight weeks (a, b) and short, brittle hair at 2 years of age (c). Light microscopy revealed trichoschisis (d; magnification 109) and polarizing microscopy showed alternating dark and light bands of hair shafts (‘tiger-tail’ banding) (e) compared to hair shafts of a healthy person (f; magnification 59).
(a)
(b)
(c)
Fig. 2. Relative post-UV cell survival rate (2, 3) in TTD5GO (a) and normal fibroblasts (b) depicted in percentage of unirradiated cells at different doses of UVC irradiation (SD). Seven thousand and five hundred cells per well were seeded. Cell culture medium caffeine was used to also test for XP variant. Relative repair capacity (n = 3; SD) in % of unirradiated firefly luciferase reporter gene plasmid and normalized to a second untreated renilla luciferase expression vector as assessed by host-cell reactivation (2, 3) of TTD5GO cells and after re-introducing wild-type XPD or XPB cDNA to TTD5GO cells (c).
As TTD comprises a rare autosomal recessive, extremely heterogeneous, multisystem disorder characterized by sulfur-deficient brittle hair, mental and growth retardation, nail abnormalities, ichthyosis, ocular and skeletal abnormalities, and recurrent infections (4, 6–8), our case highlights the necessity of regular interdisciplinary follow-up examinations to identify orphan diseases and guide families. The xeroderma pigmentosum (XP) group D gene is a subunit of the
DNA repair/transcription factor TFIIH. XPD mutations in patients with TTD seem to predominantly affect transcription, whereas XPD mutations in patients with XP primarily interfere with DNA repair (4, 9). Therefore, unlike patients with XP, patients with TTD are not skin cancer prone and the clinical course is determined by the involvement of other organs and mortality is mainly due to severe systemic infections (4, 8).
Photodermatol Photoimmunol Photomed 2016; 32: 110–112 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
111
Letter to the Editor
REFERENCES 1. Price VH, Odom RB, Ward WH, Jones FT. Trichothiodystrophy: sulfur-deficient brittle hair as a marker for a neuroectodermal symptom complex. Arch Dermatol 1980; 116: 1375–1384. 2. Emmert S, Ueda T, Zumsteg U et al. Strict sun protection results in minimal skin changes in a patient with xeroderma pigmentosum and a novel fs670?693ter mutation in XPD (ERCC2). Exp Dermatol 2009; 18: 64–68. 3. Schafer A, Gratchev A, Seebode C et al. Functional and molecular genetic analyses of nine newly identified XPD-deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex
112
phenotypes. Exp Dermatol 2013; 22: 486–489. 4. Itin PH, Sarasin A, Pittelkow MR. Trichothiodystrophy: Update on the sulfur-deficient brittle hair syndromes. J Am Acad Dermatol 2001; 44: 891–920; quiz 921-4. 5. Takaya K, Danks DM, Salazar ER, Cleaver JE, Weber CA. DNA repair characteristics and mutations in the ERCC2 DNA repair and transcription gene in a trichothiodystrophy patient. Hum Mutat 1997; 9: 519–525. 6. Lehmann J, Schubert S, Emmert S. Xeroderma pigmentosum: diagnostic procedures, interdisciplinary patient care,
and novel therapeutic approaches. J Dtsch Dermatol Ges 2014; 12: 867–872. 7. Traupe H, Fischer J, Oji V. Nonsyndromic types of ichthyoses – an update. J Dtsch Dermatol Ges 2014; 12: 109–121. 8. Faghri S, Tamura D, Kraemer KH, DiGiovanna JJ. Trichothiodystrophy: a systemic review of 112 published cases characterises a wide spectrum of clinical manifestations. J Med Genet 2008; 45: 609–621. 9. Lehmann AR. The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev 2001; 15: 15–23.
Photodermatol Photoimmunol Photomed 2016; 32: 110–112 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
LETTER TO THE EDITOR
Photosensitive form of trichothiodystrophy associated with a novel mutation in the XPD gene € rner3, Knut Brockmann4, Birka Brauns1,2, Steffen Schubert1, Janin Lehmann1, Petra Laspe1, Andrea Ko 1,5 1,2 € n & Steffen Emmert Michael P. Scho
1
Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University, € ttingen, Germany. Go 2 Clinic for Dermatology and Venereology, University Medical Center Rostock, Rostock, Germany. 3 DWI – Leibniz Institute for Interactive Materials, Aachen, Germany. 4 Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center, Georg August University, € ttingen, Germany. Go 5 Lower Saxony Institute of Occupational Dermatology, € ttingen and University of University Medical Center Go € ck, Osnabru € ck, Germany. Osnabru
Correspondence: Steffen Emmert, M.D., Clinic for Dermatology and Venereology, University Medical Center Rostock, D-18057 Rostock, Germany. Tel: +49 (0)381 4949701 Fax: 49 (0)381 4949702 e-mail: [email protected]
Accepted for publication: 27 October 2015
Funding sources: €chsische This work was supported by a grant from the Niedersa Krebsgesellschaft e.V. (to SE and SS).
Conflicts of interest: None.
To the Editor, The term ‘trichothiodystrophy’ (TTD) was introduced by Price et al. (1) in 1980 to describe a group of rare autosomal recessive disorders characterized by sulfur-deficient brittle hair and other neuroectodermal symptoms. An eight-week-old boy was referred to our clinic with dry, scaly skin on the trunk and dorsal extremities 110
sparing the flexures (Fig. 1a,b). In the second year of his life, however, the patient additionally exhibited short, brittle hair (Fig. 1c) and nails, nail dystrophy, photosensitivity, mild delay of motor and speech development, and marked ataxia. At age 2 years, weight, length, and head circumference were within normal ranges. There were no ocular defects. He also suffered from frequent febrile infections of the upper respiratory system. Analysis of the patient’s hair by light microscopy revealed transverse fractures (trichoschisis) (Fig. 1d). Alternating dark and light bands of his hair shafts (‘tiger-tail’ banding) were discovered using polarizing microscopy (Fig. 1e,f). Subsequently, amino acid analysis of hydrolyzed hairs showed a markedly reduced cystine content of 3.5 mol/100 mol compared to 9.4 mol/100 mol in the control hair of a healthy boy. This characteristic constellation led to the diagnosis of trichothiodystrophy (TTD). Magnetic resonance imaging of the brain revealed mild diffuse T2-hyperintensity of supratentorial white matter consistent with dysmyelination, as described previously in TTD. We established a fibroblast cell line (TTD5GO) from a skin punch biopsy. After irradiation with 30 J/m2 UVC, the cells showed a reduced relative post-UV cell survival (% of nonirradiated cells) (2, 3) rate of only 61.4 2.2% compared to >75% of normal fibroblasts (Fig. 2a,b). As most photosensitive forms of TTD are predominantly caused by defects in the xeroderma pigmentosum group D gene (XPD/ERCC2) rather than by mutations in XPB/ ERCC3 or TTDA (4), we performed XPD gene sequencing. Indeed, the patient was compound heterozygous for two mutations in XPD: c.2164C>T (p.R722W; from father), described at least in 13 patients and known TTD-causing (2, 3) and a novel TTD-associated c.2174C>T mutation (p.A725V; from mother). Interestingly, another amino acid exchange at the same position (p.A725P) has been previously identified as TTD-causing (5) in another patient. Re-introducing wild-type XPD cDNA into TTD5GO cells increased their repair capacity threefold as assessed by host-cell reactivation (3) indicating complementation by XPD (Fig. 2c). ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd doi:10.1111/phpp.12225
Letter to the Editor
(a)
(d)
(b)
(e)
(c)
(f)
Fig. 1. Clinical features of trichothiodystrophy in a young boy showing dry, scaly skin on the trunk and dorsal extremities sparing the flexures at eight weeks (a, b) and short, brittle hair at 2 years of age (c). Light microscopy revealed trichoschisis (d; magnification 109) and polarizing microscopy showed alternating dark and light bands of hair shafts (‘tiger-tail’ banding) (e) compared to hair shafts of a healthy person (f; magnification 59).
(a)
(b)
(c)
Fig. 2. Relative post-UV cell survival rate (2, 3) in TTD5GO (a) and normal fibroblasts (b) depicted in percentage of unirradiated cells at different doses of UVC irradiation (SD). Seven thousand and five hundred cells per well were seeded. Cell culture medium caffeine was used to also test for XP variant. Relative repair capacity (n = 3; SD) in % of unirradiated firefly luciferase reporter gene plasmid and normalized to a second untreated renilla luciferase expression vector as assessed by host-cell reactivation (2, 3) of TTD5GO cells and after re-introducing wild-type XPD or XPB cDNA to TTD5GO cells (c).
As TTD comprises a rare autosomal recessive, extremely heterogeneous, multisystem disorder characterized by sulfur-deficient brittle hair, mental and growth retardation, nail abnormalities, ichthyosis, ocular and skeletal abnormalities, and recurrent infections (4, 6–8), our case highlights the necessity of regular interdisciplinary follow-up examinations to identify orphan diseases and guide families. The xeroderma pigmentosum (XP) group D gene is a subunit of the
DNA repair/transcription factor TFIIH. XPD mutations in patients with TTD seem to predominantly affect transcription, whereas XPD mutations in patients with XP primarily interfere with DNA repair (4, 9). Therefore, unlike patients with XP, patients with TTD are not skin cancer prone and the clinical course is determined by the involvement of other organs and mortality is mainly due to severe systemic infections (4, 8).
Photodermatol Photoimmunol Photomed 2016; 32: 110–112 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
111
Letter to the Editor
REFERENCES 1. Price VH, Odom RB, Ward WH, Jones FT. Trichothiodystrophy: sulfur-deficient brittle hair as a marker for a neuroectodermal symptom complex. Arch Dermatol 1980; 116: 1375–1384. 2. Emmert S, Ueda T, Zumsteg U et al. Strict sun protection results in minimal skin changes in a patient with xeroderma pigmentosum and a novel fs670?693ter mutation in XPD (ERCC2). Exp Dermatol 2009; 18: 64–68. 3. Schafer A, Gratchev A, Seebode C et al. Functional and molecular genetic analyses of nine newly identified XPD-deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex
112
phenotypes. Exp Dermatol 2013; 22: 486–489. 4. Itin PH, Sarasin A, Pittelkow MR. Trichothiodystrophy: Update on the sulfur-deficient brittle hair syndromes. J Am Acad Dermatol 2001; 44: 891–920; quiz 921-4. 5. Takaya K, Danks DM, Salazar ER, Cleaver JE, Weber CA. DNA repair characteristics and mutations in the ERCC2 DNA repair and transcription gene in a trichothiodystrophy patient. Hum Mutat 1997; 9: 519–525. 6. Lehmann J, Schubert S, Emmert S. Xeroderma pigmentosum: diagnostic procedures, interdisciplinary patient care,
and novel therapeutic approaches. J Dtsch Dermatol Ges 2014; 12: 867–872. 7. Traupe H, Fischer J, Oji V. Nonsyndromic types of ichthyoses – an update. J Dtsch Dermatol Ges 2014; 12: 109–121. 8. Faghri S, Tamura D, Kraemer KH, DiGiovanna JJ. Trichothiodystrophy: a systemic review of 112 published cases characterises a wide spectrum of clinical manifestations. J Med Genet 2008; 45: 609–621. 9. Lehmann AR. The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev 2001; 15: 15–23.
Photodermatol Photoimmunol Photomed 2016; 32: 110–112 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
