Letters to the Editor
was considered and IFX was replaced with ADA. The patient’s PASI was 37.3 immediately before ADA therapy. Despite the initiation of ADA, the PASI continued to rise; therefore, MTX was added 10 weeks after commencement of ADA. No remarkable deterioration was observed up to week 64 of the follow-up period. As in Figure 1(b), with the formation of ATI, the serum IFX concentration dropped steeply to an undetectable level. AAA was detected at week 18 of ADA therapy, and declined to an undetectable level at week 46, 24 weeks after the addition of MTX. ADA concentrations stayed within the effective range throughout ADA therapy. The combination of ADA and MTX may be instrumental in stabilizing the effect of ADA against the emergence of AAA even after the formation of AAA.
CONFLICT OF INTEREST:
There is no conflict of interest
to declare.
Hiroshi KAWAKAMI, Tatsurou MAEDA, Namiko ABE, Yuka MATSUMOTO, Yoshihiko MITSUHASHI, Ryoji TSUBOI, Yukari OKUBO Department of Dermatology, Tokyo Medical University, Tokyo, Japan doi: 10.1111/1346-8138.12704
REFERENCES 1 Zangrilli A, Papoutaki M, Talamonti M, Chimenti S. Long-term efficacy of adalimumab in generalized pustular psoriasis. J Dermatolog Treat 2008; 19(3): 185–187. 2 Chaudhari U, Romano P, Chaudhari U1, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial. Lancet 2001; 357: 1842–1847. 3 Adisen E, Aral A, Aybay C, Gurer MA. Anti-infliximab antibody status and its relation to clinical response in psoriatic patients: a pilot study. J Dermatol 2010; 37: 703–713. 4 Krieckaet CL, Nurmohamed MT, Molbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis 2012; 71: 1914–1915.
Novel missense mutation in the COL3A1 gene caused vascular Ehlers–Danlos syndrome in a Chinese family Dear Editor, The vascular type of Ehlers–Danlos syndrome (EDS) is an autosomal dominant disorder caused by mutations of type III procollagen gene (COL3A1), located at 2q31-q32, which contains 51 exons.1 It is characterized by easy bruising, thin transparent skin, characteristic facial features, and fatal rupture of the arteries, uterus or intestines, the severity of clinical features varies widely. According to the ClinVar Database (http://www.ncbi.nlm.nih.gov/clinvar/), 434 pathogenic/likely pathogenic variations in COL3A1 have been described (updated in August 2014), including 280 missense and 93 splicing site variations. Here, we report a novel missense mutation c.2176G>C in the COL3A1 gene in a family with vascular EDS. This study consisted of three affected individuals, nine unaffected relatives from a Chinese family clinically characterized as vascular EDS (Fig. 1a), and 239 unrelated controls. The proband (P1, II-14) was 45 years old, with a left hip artery hemorrhage, diagnosed as vascular EDS. He had a lanky frame, thin translucent skin with prominent subcutane-
ous venous patterning, hypermobility of all thumb joints and hyperextensible distal interphalangeal joints of the fingers (Fig. 1b). Patient 2 (III-3) was a 39-year-old woman with short stature, low weight and characteristic facial features (Fig. 1c). She had a history of gastrorrhagia and also had thin translucent skin. Her mother and brother had both died of vascular EDS. Besides hypermobility of the small joints, II5 had prominent staring eyes with periorbital pigmentation and fine telangiectasia of the eyelids. Thus, the clinical characteristics of affected individuals in this family were highly heterogeneous. We selected 11 mutation hotspots of the COL3A1 gene for direct sequencing, which are summarized according to the Human Gene Mutation Database (http://www.hgmd.org/) and reports in the Chinese population. In this family, three affected individuals and one healthy member, IV-1, were identified to have a novel missense mutation c.2176G>C in the COL3A1 gene, while the mutation was not found in other unaffected family members and controls (Fig. 1d). Interestingly, the same amino acid change, but different nucleotide
Correspondence: Zhengmao Hu, Ph.D., and Qian Pan, M.S., State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China. Emails: [email protected] and [email protected] *These authors contributed equally to this study.
© 2014 Japanese Dermatological Association
95
Letters to the Editor
(a)
(b)
(d)
(c)
Figure 1. (a) Pedigree of the type IV Ehlers–Danlos syndrome family. Family members participating in this study are marked with asterisk above left. (b) Clinical features of proband (long, slim fingers and prominent joints). (c) Characteristic facial appearance of III-3 (pinched nose, thin lips, prominent staring eyes with periorbital pigmentation and fine telangiectasia of eyelids, high cheekbones and sunken cheeks). (d) Direct sequencing of gDNA shows a heterozygous c.2176G>C in COL3A1.
acid change (c.2176G>A), has been reported in an 11-yearold patient, whose height was in the 50th percentile, with a slender body build, fine facial features and thin translucent skin with prominent subcutaneous venous patterning.2 The association between types of complications and specific mutations in COL3A1 remains unclear.3 As the most severe form of EDS, vascular EDS, carries a risk for arterial dissections or rupture, gastrointestinal perforations and uterine rupture during pregnancy. These complications usually develop in 25% of patients before the age of 20 years and 80% before the age of 40 years. The arterial complications are the leading cause of death in this syndrome and carry increased risks of morbidity and mortality.3–5 In this family, six individuals had sudden death at middle age (II-1, III1 and III-7 with a vascular catastrophe documented). However, IV-1, a 12-year-old girl with c.2176G>C mutation, only has small joint hyperextensibility and we will follow up on her conditions. In conclusion, we have identified a novel mutation, c.2176G>C, in the COL3A1 gene in a Chinese family with EDS type IV. Our study enriched the vascular EDS pathogenic mutation spectrum. It is intriguing to understand the heterogeneity of vascular EDS.
CONFLICT OF INTEREST:
We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, ser-
96
vice and/or company that could be construed as influencing the position presented in, or the review of, this manuscript.
Fang HE,1,2,* Xianwei WANG,3,* Xinzhang CAI,1 Hao PENG,1 Lusi ZHANG,1 Tengfei ZHU,1 Kun XIA,1 Qian PAN,1 Zhengmao HU1 1
State Key Laboratory of Medical Genetics, Central South University, Changsha, 2Xiangtan Central Hospital, Xiangtan, and 3Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China doi: 10.1111/1346-8138.12696
REFERENCES 1 Kuivaniemi H, Tromp G, Prockop DJ. Mutations in collagen genes: causes of rare and some common diseases in humans. FASEB J 1991; 5: 2052–2060. 2 Bateman JF, Chiodo AA, Weng YM, Chan D, Haan E et al. A type III collagen Gly559 to Arg helix mutation in Ehler’s-Danlos syndrome type IV. Hum Mutat 1998; 11 (Suppl 1): S257–S259. 3 Pepin M, Schwarze U, Superti-Furga A, Byers PH et al. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000; 342: 673–680. 4 Germain DP. Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis 2007; 22: 32. 5 Oderich GS, Panneton JM, Bower TC et al. The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience. J Vasc Surg 2005; 42 (1): 98–106.
© 2014 Japanese Dermatological Association
was considered and IFX was replaced with ADA. The patient’s PASI was 37.3 immediately before ADA therapy. Despite the initiation of ADA, the PASI continued to rise; therefore, MTX was added 10 weeks after commencement of ADA. No remarkable deterioration was observed up to week 64 of the follow-up period. As in Figure 1(b), with the formation of ATI, the serum IFX concentration dropped steeply to an undetectable level. AAA was detected at week 18 of ADA therapy, and declined to an undetectable level at week 46, 24 weeks after the addition of MTX. ADA concentrations stayed within the effective range throughout ADA therapy. The combination of ADA and MTX may be instrumental in stabilizing the effect of ADA against the emergence of AAA even after the formation of AAA.
CONFLICT OF INTEREST:
There is no conflict of interest
to declare.
Hiroshi KAWAKAMI, Tatsurou MAEDA, Namiko ABE, Yuka MATSUMOTO, Yoshihiko MITSUHASHI, Ryoji TSUBOI, Yukari OKUBO Department of Dermatology, Tokyo Medical University, Tokyo, Japan doi: 10.1111/1346-8138.12704
REFERENCES 1 Zangrilli A, Papoutaki M, Talamonti M, Chimenti S. Long-term efficacy of adalimumab in generalized pustular psoriasis. J Dermatolog Treat 2008; 19(3): 185–187. 2 Chaudhari U, Romano P, Chaudhari U1, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial. Lancet 2001; 357: 1842–1847. 3 Adisen E, Aral A, Aybay C, Gurer MA. Anti-infliximab antibody status and its relation to clinical response in psoriatic patients: a pilot study. J Dermatol 2010; 37: 703–713. 4 Krieckaet CL, Nurmohamed MT, Molbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis 2012; 71: 1914–1915.
Novel missense mutation in the COL3A1 gene caused vascular Ehlers–Danlos syndrome in a Chinese family Dear Editor, The vascular type of Ehlers–Danlos syndrome (EDS) is an autosomal dominant disorder caused by mutations of type III procollagen gene (COL3A1), located at 2q31-q32, which contains 51 exons.1 It is characterized by easy bruising, thin transparent skin, characteristic facial features, and fatal rupture of the arteries, uterus or intestines, the severity of clinical features varies widely. According to the ClinVar Database (http://www.ncbi.nlm.nih.gov/clinvar/), 434 pathogenic/likely pathogenic variations in COL3A1 have been described (updated in August 2014), including 280 missense and 93 splicing site variations. Here, we report a novel missense mutation c.2176G>C in the COL3A1 gene in a family with vascular EDS. This study consisted of three affected individuals, nine unaffected relatives from a Chinese family clinically characterized as vascular EDS (Fig. 1a), and 239 unrelated controls. The proband (P1, II-14) was 45 years old, with a left hip artery hemorrhage, diagnosed as vascular EDS. He had a lanky frame, thin translucent skin with prominent subcutane-
ous venous patterning, hypermobility of all thumb joints and hyperextensible distal interphalangeal joints of the fingers (Fig. 1b). Patient 2 (III-3) was a 39-year-old woman with short stature, low weight and characteristic facial features (Fig. 1c). She had a history of gastrorrhagia and also had thin translucent skin. Her mother and brother had both died of vascular EDS. Besides hypermobility of the small joints, II5 had prominent staring eyes with periorbital pigmentation and fine telangiectasia of the eyelids. Thus, the clinical characteristics of affected individuals in this family were highly heterogeneous. We selected 11 mutation hotspots of the COL3A1 gene for direct sequencing, which are summarized according to the Human Gene Mutation Database (http://www.hgmd.org/) and reports in the Chinese population. In this family, three affected individuals and one healthy member, IV-1, were identified to have a novel missense mutation c.2176G>C in the COL3A1 gene, while the mutation was not found in other unaffected family members and controls (Fig. 1d). Interestingly, the same amino acid change, but different nucleotide
Correspondence: Zhengmao Hu, Ph.D., and Qian Pan, M.S., State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China. Emails: [email protected] and [email protected] *These authors contributed equally to this study.
© 2014 Japanese Dermatological Association
95
Letters to the Editor
(a)
(b)
(d)
(c)
Figure 1. (a) Pedigree of the type IV Ehlers–Danlos syndrome family. Family members participating in this study are marked with asterisk above left. (b) Clinical features of proband (long, slim fingers and prominent joints). (c) Characteristic facial appearance of III-3 (pinched nose, thin lips, prominent staring eyes with periorbital pigmentation and fine telangiectasia of eyelids, high cheekbones and sunken cheeks). (d) Direct sequencing of gDNA shows a heterozygous c.2176G>C in COL3A1.
acid change (c.2176G>A), has been reported in an 11-yearold patient, whose height was in the 50th percentile, with a slender body build, fine facial features and thin translucent skin with prominent subcutaneous venous patterning.2 The association between types of complications and specific mutations in COL3A1 remains unclear.3 As the most severe form of EDS, vascular EDS, carries a risk for arterial dissections or rupture, gastrointestinal perforations and uterine rupture during pregnancy. These complications usually develop in 25% of patients before the age of 20 years and 80% before the age of 40 years. The arterial complications are the leading cause of death in this syndrome and carry increased risks of morbidity and mortality.3–5 In this family, six individuals had sudden death at middle age (II-1, III1 and III-7 with a vascular catastrophe documented). However, IV-1, a 12-year-old girl with c.2176G>C mutation, only has small joint hyperextensibility and we will follow up on her conditions. In conclusion, we have identified a novel mutation, c.2176G>C, in the COL3A1 gene in a Chinese family with EDS type IV. Our study enriched the vascular EDS pathogenic mutation spectrum. It is intriguing to understand the heterogeneity of vascular EDS.
CONFLICT OF INTEREST:
We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, ser-
96
vice and/or company that could be construed as influencing the position presented in, or the review of, this manuscript.
Fang HE,1,2,* Xianwei WANG,3,* Xinzhang CAI,1 Hao PENG,1 Lusi ZHANG,1 Tengfei ZHU,1 Kun XIA,1 Qian PAN,1 Zhengmao HU1 1
State Key Laboratory of Medical Genetics, Central South University, Changsha, 2Xiangtan Central Hospital, Xiangtan, and 3Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China doi: 10.1111/1346-8138.12696
REFERENCES 1 Kuivaniemi H, Tromp G, Prockop DJ. Mutations in collagen genes: causes of rare and some common diseases in humans. FASEB J 1991; 5: 2052–2060. 2 Bateman JF, Chiodo AA, Weng YM, Chan D, Haan E et al. A type III collagen Gly559 to Arg helix mutation in Ehler’s-Danlos syndrome type IV. Hum Mutat 1998; 11 (Suppl 1): S257–S259. 3 Pepin M, Schwarze U, Superti-Furga A, Byers PH et al. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000; 342: 673–680. 4 Germain DP. Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis 2007; 22: 32. 5 Oderich GS, Panneton JM, Bower TC et al. The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience. J Vasc Surg 2005; 42 (1): 98–106.
© 2014 Japanese Dermatological Association
