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lesions of IH. Systemic corticosteroids are effective for deep lesions, however, may cause infections and growth delay. These therapeutic effects are limited and various significant adverse effects have to be considered. The prolonged bulky feature of IH may not be due to residual hemangioma itself rather than the accumulation of fat tissue. Imaging studies like MRI will help to decide treatment options such as surgery, medication and “wait and see”, especially when the bulky lesions remain in children.

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CONFLICT OF INTEREST:

The authors declare that there

are no conflicts of interest.

Akihiko UCHIYAMA, Atsushi TAMURA, Okada ETSUKO, Sei-ichiro MOTEGI, Osamu ISHIKAWA Figure 1. Physical examination. (a) Multiple, reddish tumors with a subcutaneous mass covering almost the entire right cheek. Initial visit at 3 months of age. (b) Clinical features at the age of 7 months showing enlargement in size and bluish discoloration over the subcutaneous component. (c) Clinical features at the age of 12 years showing residual subcutaneous mass covered with telangiectatic atrophic scar on the right cheek. (d) Magnetic resonance imaging of the face showing thickened subcutaneous fat tissue in the right cheek. (e) Histological examination of the resected tissue. The residual mass was composed of mature adipose tissue including a few mature blood vessels and fibrosis (hematoxylin–eosin, original magnification 9200). (f) Postoperative view at 5 months showing improved aesthetic results.

Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan doi: 10.1111/1346-8138.12457

REFERENCES 1 Jinnin M, Ishihara T, Boye E, Olsen BR. Recent progress in studies of infantile hemangioma. J Dermatol 2010; 37: 939–955. 2 Wahrman JE, Honig PJ. Hemangiomas. Pediatr Rev 1994; 15: 266– 271. 3 Chan LK, Smith GC, Quaba AA. The management of periorbital fat excess in haemangioma involution. J Plast Reconstr Aesthet Surg 2008; 61: 133–137.

Late-onset Brooke–Spiegler syndrome with family histories of various cancers Dear Editor, Brooke–Spiegler syndrome (BSS) is an autosomal dominant hereditary disease, exhibiting multiple adnexal tumors, namely, cylindromas, trichoepitheliomas and spiradenomas. Mutation of the CYLD gene, a tumor suppressor located on chromosome 16, is responsible for BSS, and a number of mutations have been identified.1 We report a late-onset case of sporadic BSS with family histories of various internal cancers. A 57-year-old Japanese woman presented with a 6-year history of asymptomatic nodule on the scalp. The patient had no medical history, while hepatocellular carcinoma (HCC) developed in her father and sister, uterine cancer in her mother, gastric cancer in her brother and another sister, and renal cell

carcinoma in another brother. Physical examination revealed a well-circumscribed nodule 10 mm 9 13 mm in size (Fig. 1a), which was histopathologically confirmed as cylindroma (Fig. 1b). In the following 12 years, the patient developed cribriform trichoblastoma (trichoepithelioma) (Fig. 1c,d), cylindromas, spiradenoma (Fig. 1e,f) and cylindrospiradenoma (Fig. 1g,h) on various sites. Because the patient described that her son had similar skin lesions, we performed sequence analysis of the CYLD gene using DNA samples taken from both peripheral blood and cylindrospiradenoma with the patient’s informed consent and with approval of the ethics committee of Kurume University. Heterozygous and homozygous mutations (c.2272C>T, p.R758X) were

Correspondence: Takashi Hashimoto, M.D., Department of Dermatology, Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan. Email: [email protected]

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identified in exon 17 from peripheral blood DNA and tumor DNA, respectively (Fig. 1i,j). Loss of heterozygosity (LOH) in the tumor DNA was testified by microsatellite marker studies using D16S3136, D16S3034 and D16S3140, all of which locate around the CYLD gene locus. The patient refused genetic studies in other family members. The present case is the second BSS case with LOH of 2272C>T in the CYLD gene. A recurrent nonsense mutation

© 2014 Japanese Dermatological Association

Figure 1. (a) Red nodule on the scalp at the first visit. (b) Histopathological examination of the skin lesion in (a) revealed relatively well-circumscribed discrete aggregations of basaloid cells, which were surrounded by rims of homogeneous basement membrane material and were situated in close proximity to one another with jigsaw puzzle appearance, in the dermis and subcutis (hematoxylin–eosin [HE], original magnification 9100). (c) Pigmented nodule on the cheek. (d) Histopathological examination of the skin lesion in (c) revealed large aggregations of basaloid cells with sieve-like pattern, surrounded by abundant fibrotic stroma with foci of follicular differentiation in the form of germs and rudimentary papillae at the periphery. The diagnosis of cribriform trichoblastoma (trichoepithelioma) was made (HE, 9200). (e) Small nodules next to ala nasi. (f) Histopathological examination of the skin lesion in (e) revealed aggregations composed of small dark cells and larger pale cells with lymphocytic infiltrate within the aggregations. The diagnosis of spiradenoma was made (HE, 9100). (g) Red nodule on the forehead at the third visit. (h) Histopathological examination of the skin lesion in (g) revealed areas typical of both cylindroma and spiradenoma. The diagnosis of cylindrospiradenoma was made (HE, 9100). (i) Mutation analysis of exon 17 of the CYLD gene from a peripheral blood sample of the patient identified a heterozygous mutation c.2272C>T. (j) The sequence analysis using tumor DNA showed only the mutant allele. The sequence analysis using DNA isolated from normal skin of the patient showed both mutant and wild-type alleles.

c.2272C>T has been identified in six BSS families.1,2 Among these families, somatic mutations in tumor DNA were studied in nine tumors in three members from two families.1 LOH of c.2272C>T was most commonly detected, while 2630delA was found in one trichoepithelioma. Intriguingly, the patient who had trichoepithelioma showing 2630delA also had another trichoepithelioma, which showed LOH of c.2272C>T. Similarly, each appendage tumor in our case might have had different somatic mutations. CYLD is a deubiquitinating enzyme that downregulates the transcription factor nuclear factor (NF)-jB activated through specific tumor necrosis factor receptors.3 Because NF-jB is required for appropriate cellular homeostasis of skin appendages, mutations in the CYLD gene are speculated to correlate with appendage tumor formation. NF-jB activation is also connected with multiple aspects of carcinogenesis, particularly in HCC and colon cancer.4 Recently, CYLD mRNA expression was found to be reduced in HCC and colon cancer cell lines, and CYLD expression was reduced or lost in cell lines and tissues of HCC and colon cancer. These findings raised the possibility that the patient’s family histories of various cancers may be related to loss of the CYLD gene function. Although malignant transformation of appendage tumors in BSS has occasionally been reported,5 BSS cases with family histories of various internal cancers have never been reported. Further investigations are required to elucidate the role of NF-jB in BSS and various cancers.

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ACKNOWLEDGMENTS: We gratefully appreciate the secretarial work of Ms Tomoko Tashima, Ms Mami Nishida and Ms Shoko Nakamura. We thank the patient for her participation. CONFLICT OF INTEREST:

None.

Mitsuhiro MATSUDA,1,2 Chika OHATA,1,2 Takahiro HAMADA,1,2 Naoki OISO,3 Daisuke TSURUTA,4 Minao FURUMURA,1,2 Takashi HASHIMOTO1,2 1

Department of Dermatology, Kurume University School of Medicine 2 Kurume University Institute of Cutaneous Cell Biology, Fukuoka, 3 Department of Dermatology, Kinki University Faculty of Medicine, Osaka-Sayama, and 4Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan doi: 10.1111/1346-8138.12451

REFERENCES 1 Grossmann P, Vanecek T, Steiner P et al. Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with Brooke-Spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens. Am J Dermatopathol 2013; 35: 34–44. 2 Zhang G, Huang Y, Yan K et al. Diverse phenotype of BrookeSpiegler syndrome associated with a nonsense mutation in the CYLD tumor suppressor gene. Exp Dermatol 2006; 15: 966–970. 3 Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 2003; 424: 793–796. 4 Hellerbrand C, Bumes E, Bataille F, Dietmaier W, Massoumi R, Bosserhoff AK. Reduced expression of CYLD in human colon and hepatocellular carcinomas. Carcinogenesis 2007; 28: 21–27. 5 Kostler E, Schonlebe J, Mentzel T, Haroske G, Wollina U. Psoriasis and Brooke-Spiegler syndrome with multiple malignancies. J Eur Acad Dermatol Venereol 2005; 19: 380–381.

Novel G144D mutation of the GLA gene in a Chinese patient with Fabry disease Dear Editor Fabry disease (FD; OMIM:301500), alternatively named angiokeratoma corporis diffusum, is a systemic disease manifested as progressive renal failure, cardiac disease, cerebrovascular disease, small-fiber peripheral neuropathy and skin lesions.1 It is an X-linked recessive disorder caused by deficiency in alpha-galactosidase A (GLA; OMIM:300644).2 Heterozygous females are usually asymptomatic because they can express a normal level of GLA activity owing to X-chromosomal inactivation. To identify pre-symptomatic females with FD, direct sequencing analysis of GLA gene was performed in a Chinese Han patient. The patient was a 26-year-old sporadic case. Clinical examination revealed small, asymptomatic, dark red to black papules on her left lower extremity (Fig. 1a). She suffered from chronic diarrhea with cramping epigastric pain, and a sense of tingling in the extremities since 2007. Skin biopsy showed dilated thin walled blood vessels lined by a layer of endothelial cells in the papillary dermis (Fig. 1b, c). Routine urinalysis and kidney function test showed normal findings. The leukocyte a-Gal A enzyme activity of the patient and her mother were normal, with the average value 12.5 nmol/(h.mg pr)and 16.9 nmol/ (h.mg pr) respectively. Approval for this study was obtained from the ethics committee of Anhui Medical University. After informed consent, genomic DNA was isolated from the peripheral blood of the patient. All 7 exons and flanking introns of the GLA gene were amplified by polymerase chain reaction as described previously.3 We reporte here a novel c.431G>A transition leading to

p.G144D amino acid replacement in this patient (Fig. 1d, e). This mutation was not identified in additional whole exome sequencing data of 676 unrelated controls.4 The p.G144D change was classified as “probably damaging” with a score of 0.99 using Polyphen2 software (Harvard Medical School, Boston, MA, USA), indicating this mutation maybe involved in the dysfunction of enzyme a-Gal A. Currently, about 600 mutations have been identified worldwide in patients with FD (Human gene mutation database site, http://www.hgmd.org/). About 70% of them are missense or nonsense, whereas the remainder consist of splicing regulatory, small or gross insertion or deletion mutations. In this study, c.431G>A missense mutation brings the total mutations affecting codon 144 to 2, as the c.431G>T transversion leading to p.G144V has been reported before.5 It is commonly believed that Glycine plays an important role in stabilizing protein structure. Thus the p.G144D change may influence the conformational flexibility and dynamic properties of a-Gal A protein. The clinical and genetic findings help in differentiating the current case from angiokeratoma circumscriptum. As the rarest angiokeratomas types, angiokeratoma circumscriptum is nevoid with an onset in early life. It is characterized by aggregates of hyperkeratic erythematous papules and nodules, which may coalesce to form verrucous plaques. Histopathologically, it shows hyperkeratosis, irregular acanthosis, papillomatosis, and dilated capillary spaces in reticular dermis. Genetically, there is no obvious hereditary tendency for angiokeratoma circumscriptum, while FD is caused by abnormalities in the GLA gene as indicated in this study.

Correspondence: Dr Sen Yang, M.D., Ph.D., Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China. Email: [email protected] The first two authors contributed equally to this work, and should be considered joint first authors.

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Late-onset Brooke-Spiegler syndrome with family histories of various cancers.

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