A
B
C
D
type 3 (PAX3), type 4A (EDNRB), type 4B (EDN3) and type 4C (SOX10) [10]. Taibjee et al. summarized cases of PM in relationship with chromosomal abnormalities and co-localizing genes, including PAX3, SLUG, EDNRB, EDN3, and SOX10 [5]. In our case, a somatic mutation or epigenetic alteration might have occurred during developing pathways of mesodermal and/or ectodermal derivatives in the chromosomal regions containing a gene associated with auditory-pigmentary abnormalities. Clinical features of the serrated and irregular shapes represent overlapping of ND in our case of PM of the hypopigmented type. Thus, it seems reasonable to categorize ND as skin-limited hypopigmented PM. Disclosure. Financial support: none. Conflict of interest: none.
Figure 1. Clinical pictures of A, B) linear and patchy hypopigmented macules along Blaschko’s lines with serrated and irregular borders on the right side of the neck to the upper chest (arrows), C) the right nape to the upper back (bold arrows) and left nape (arrow). D) The left side of the neck had normal color.
The definite diagnosis for hypopigmented PM is based on non-hereditary cutaneous hypopigmented linear streaks or patches involving more than two body segments and one or more nervous or musculoskeletal anomalies [2]. Nevus depigmentosus (ND) consists of a hypopigmented area distributed as an isolated patch, a unilateral band or a streak, or multiple whorls or streaks [6-8]. The type of multiple whorls or streaks is usually limited in cases without extracutaneous anomalies. ND is usually circumscribed with serrated and irregular shapes, while hypopigmented PM commonly presents straight or circular borders. The diagnostic criteria for HI (hypopigmented PM) proposed by Ruiz-Maldonado et al. are still applicable, because the presence of one or more nervous or musculoskeletal anomalies is required [2]. In the present case, the serrated and irregular shapes mimicked ND but the diagnosis of hypopigmented PM was based on the bilateral hypopigmented lesions associated with congenital sensorineural hearing loss. The auditory brain stem response is useful to confirm congenital sensorineural hearing loss. Ruiz-Maldonado et al. summarized 41 cases of hypopigmented PM and characterized them as linear lesions along Blaschko’s lines in 26, patchy lesions in 9, and patchy and linear lesions in 6 cases [2]. Patchy lesions in PM of the hypopigmented type tend to have squared or rounded rather than linear distribution [2]. To our knowledge, no cases of ND with hearing loss have been reported. Coexistence of cutaneous and nervous system abnormalities suggests the occurrence of a somatic mutation or epigenetic alteration. Our recent survey showed that PM (reported as HI) was present in 1% of all hypopigmented disorders in Japan and ND in 6% [9]. The relatively high frequency of PM and ND was associated with the existence of many pigmentation-associated genes. Blaschko’s lines seem to depict pathways of mesodermal and/or ectodermal derivatives. Segmental distribution reflects mosaicism affecting mesodermal derivatives. Differential diagnoses include auditory-pigmentary abnormalities of Waardenburg syndrome type 1 (caused by a mutation in PAX3), type 2A (MITF), type 2D (SLUG (SNAI2)), type 2E (SOX10), EJD, vol. 24, n◦ 6, November-December 2014
Department of Dermatology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
Naoki OISO Akira KAWADA
1. Ito M. Studies on melanin X1. Incontinentia pigmenti achrominans. A singular case of nevus depigmentosus systematicus bilateralis. Tohoku J Exp Med 1952; 55: 57-9. 2. Ruiz-Maldonado R, Toussaint S, Tamayo L, Laterza A, del Castillo V. Hypomelanosis of Ito: diagnostic criteria and report of 41 cases. Pediatr Dermatol 1992; 9: 1-10. 3. Oiso N, Amatsu A, Kawara S, Kawada A. Pigmentary mosaicism with hyperpigmented streaks on the palmoplantar lesion associated with balanced X; autosome translocations t(X; 9)(p11.21; q34.1). J Eur Acad Dermatol Venereol 2009; 23: 359-61. 4. Kuster W, Happle R. ‘Hypomelanosis of Ito’ and mosaicism. In Nordlund JJ, Boissy E, Hearing VJ, King RA, Oetting WS, Ortonne JP, eds. The Pigmentary System: Physiology and Pathophisiology, 2nd edn. Blackwell Publishing Ltd, Oxford, 2006: 636-45. 5. Taibjee SM, Bennett DC, Moss C. Abnormal pigmentation in hypomelanosis of Ito and pigmentary mosaicism: the role of pigmentary genes. Br J Dermatol 2004; 151: 269-82. 6. Xu AE, Huang B, Li YW, Wang P, Shen H. Clinical, histopathological and ultrastructural characteristics of naevus depigmentosus. Clin Exp Dermatol 2008; 33: 400-5. 7. Oiso N, Kawada A. The diagnostic usefulness of dermoscopy for nevus depigmentosus. Eur J Dermatol 2011; 21: 639-40. 8. Oiso N, Nomi N, Fukai K, et al. Nevus depigmentosus with pale skin, yellow-brown hair and a bright brown iris. Eur J Dermatol 2014; 24: 406-7. 9. Oiso N, Suzuki T, Wataya-Kaneda M, et al. Guidelines for the diagnosis and treatment of vitiligo in Japan. J Dermatol 2013; 40: 34454. 10. Oiso N, Fukai K, Kawada A, Suzuki T. Piebaldism. J Dermatol 2013; 40: 330-5. doi:10.1684/ejd.2014.2424
Three cases of elastofibroma with immunohistochemical analysis of microfibrillar components Elastofibroma is a rare benign tumor, localized, in most cases, to the infrascapular region [1, 2]. Elastin-specific
691
staining reveals multiple globular or bead-like structures in cross sections [1, 2]. Electron microscopy reveals abnormal flower-like aggregates of elastic fibers, with a central core of elastin surrounded by radiating “petals” of granular and filamentous material, suggesting that the structure and organization of the microfibrils are abnormal [3]. We discuss here three cases of elastofibroma with immunohistochemical analysis of microfibrillar components. Fibulin 2-, 3- and 5- and hemicentin-specific antibodies reacted positively with bead-like structures. Antibodies against latent TGF-binding proteins (LTBPs)1 and -2 also reacted with these structures. Case 1 In January 2007, a 74-year-old female presented for skin cancer screening complaining of a symptomless and slowly growing mass on her left shoulder that she had first noticed two years previously. The tumor was hard and elastic (figure 1A). Magnetic resonance imaging (MRI) revealed a lesion, between the latissimus dorsi muscle and the thoracic-rib infrascapular region, of 70 × 22 × 72 mm. Signal intensity resembled that of skeletal muscle, with regions of alternating high and low signal intensities on T1 and T2 weighted spin-echo sequences, and was typical of elastofibroma. A biopsy specimen contained globular or bead-like structures that stained positively with elas-
(A)
(B)
(C)
(D)
(E)
(F)
(G)
(H)
(I)
(J)
(K)
(L)
(M)
(N)
(O)
Figure 1. Elastic hard, poorly circumscribed tumor around the left scapular area (A). Elastica van Gieson staining (B-D) and immunohistochemical analysis with microfibril-specific antibodies against fibulin-1 (E), -2 (F) -3 (G), -4 (H) and -5 (I); hemicentin (J); LTBP-1 (K), -2 (L), -3 (M) and -4 (N); and fibronectin (O). Original magnification × 40 (B), ×100 (C), ×400 (D-O).
692
tica van Gieson stain (figures 1B-D). After a diagnosis of elastofibroma, the tumor was resected surgically. Case 2 A 74-year-old female presented with a painful and slowly growing mass on her left shoulder in March 2008. MRI revealed a lesion between the latissimus dorsi muscle and the thoracic-rib infrascapular area of 60 × 20 × 60 mm. The imaging features resembled those in case 1. After biopsy and a diagnosis of elastofibroma, the tumor was resected surgically in May 2008. Case 3 A 64-year-old male presented with a slowly growing mass on each shoulder that he had noticed for one or two years. MRI revealed a right-side lesion of 83 × 33 mm and a left-side lesion of 73 × 25 mm. After a diagnosis of elastofibroma, both tumors were resected surgically in January 2011. To identify the microfibrillar components that might contribute to the formation of elastofibroma, we performed immunohistochemical staining with microfibrillar component-specific antibodies [4, 5]. In contrast to antibodies against fibulins 1 and 4, antibodies against fibulins 2, 3 and 5 and hemicentin reacted positively with bead-like structures (figures 1E-J). Antibodies against latent TGFbinding proteins (LTBPs)-1 and 2, but not against LTBP-3 and -4, reacted with globular structures (figures 1K-N). Fibronectin-specific antibodies did not react with bead-like structures (figure 1O). To examine whether aging might be important in the formation of elastofibromas, we performed immunohistochemical staining with antibodies against a Dbeta-Asp containing peptide [6]. No staining with these antibodies was detected in elastic structures in resected specimens (data not shown). We detected at least four members of the fibulin family and two kinds of LTBP in our elastofibromas. Elastofibroma often occurs in farmers and manual laborers. Moreover shear stress has been reported to induce activation of TGF1 via LTBP-1, and TGF1 might contribute to the formation and enlargement of this tumor. LTBP-2, which does not bind TGF, might be an indirect negative modulator of storage of the large latent TGF1 complex. The deposition of LTBP within microfibrils does not occur in the absence of fibrillin-1 and fibronectin [7]. We failed to detect fibronectin in this study. The function of hemicentin in the dermis is unclear, but hemicentin has been reported in mouse epidermis, hair follicles and sebaceous glands after immunostaining with antibodies against nematode hemicentin [8]. Biologically rare D-aspartyl (D-Asp) residues have been found in proteins of various tissues, including the skin, of elderly humans. Aspartic acid is the most easily racemizable amino acid and D-Asp might be formed by spontaneous racemization in metabolically inactive tissues during chronological aging. Formation of D-Asp is accompanied by isomerization of natural alpha-Asp to the abnormal beta-Asp [9]. D-Beta-Asp can be detected in sun-damaged dermis and one of the sites of its formation is reported to be elastin [10]. In elastofibroma, this reaction might not contribute to aggregation of elastic components. In summary, the bead-like structures in elastofibroma appear to be composed of several fundamental macromolecules, fibulins and LTBPs. The molecular organization of these components and signature abnormalities of this disease including hereditary factor(s) remain to be elucidated. EJD, vol. 24, n◦ 6, November-December 2014
Disclosure. Acknowledgment: The antibodies against LTBP1 was kindly provided by Prof. Heldin (Ludwig Institute for Cancer Research, Sweden). Financial support: none. Conflict of interest: none. 1
Department of Plastic Surgery Department of Dermatology, 3 Department of Matrix Medicine, Faculty of Medicine, Oita University, Hasama, Yufu, 879-5593, Japan 4 Research Reactor Institute, Kyoto University, Osaka, Japan 2
Miyuki UEHARA1 Kaho MATSUDA1 Aiko KATO1 Seiichi SATO1 Fumiaki SHIMIZU1 Miwako OOATARI1 Yoshitaka KAI2 Hiromitsu SHIMADA2 Yutaka HATANO2 Osamu OKAMOTO2 Kazumoto KATAGIRI2 Takako SASAKI3 Noriko FUJII4 Sakuhei FUJIWARA2
1. Jarvi O, Saxen E. Elastofibroma dorse. Acta Pathol Microbiol Scand Suppl 1961; 51(Suppl 144): 83-4. 2. Nagamine N, Nohara Y, Ito E. Elastofibroma in Okinawa. A clinicopathologic study of 170 cases. Cancer 1982; 50: 1794-805. 3. Kahn HJ, Hanna WM. “Aberrant elastic” in elastofibroma: an immunohistochemical and ultrastructural study. Ultrastruct Pathol 1995; 19: 45-50. 4. Giltay R, Timpl R, Kostka G. Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4. Matrix Biol 1999; 18: 469-80. 5. Kadoya K, Sasaki T, Kostka G, et al. Fibulin-5 deposition in human skin: decrease with ageing and ultraviolet B exposure and increase in solar elastosis. Br J Dermatol 2005; 153: 607-12. 6. Motoie R, Fujii N, Tsunoda S, et al. Localization of D-bAspartyl Residue-Containing Proteins in Various Tissues. Int J Mol Sci 2009; 10: 1999-2009. 7. Baldwin AK, Simpson A, Steer R, et al. Elastic fibres in health and disease. Expert Rev Mol Med 2013; 15: e8. doi: 10.1017/erm.2013.9. 8. Xu X, Dong C, Vogel BE. Hemicentins assemble on diverse epithelia in the mouse. J Histochem Cytochem 2007; 55: 119-26. 9. Fujii N, Harada K, Momose Y, et al. D-amino acid formation induced by a chiral field within a human lens protein during aging. Biophys Biochem Res Commun 1999; 263: 322-6. 10. Fujii N, Tajima S, Tanaka N, et al. The presence of D-beta-aspartic acid-containing peptides in elastic fibers of sun-damaged skin: A potent marker for ultraviolet-induced skin aging. Biochem Biophys Res Comm 2002; 294: 1047-51. doi:10.1684/ejd.2014.2427
A frameshift mutation in the ADAR gene in a Korean family with dyschromatosis symmetrica hereditaria Dyschromatosis symmetrica hereditaria (DSH; MIM 127400) is a rare autosomal dominant skin disorder characterized by a mixture of hyper- and hypopigmented macules on the dorsal surface of the extremities and face. Onset of the disease is usually during infancy or early childhood. EJD, vol. 24, n◦ 6, November-December 2014
Dyschromatosis stops spreading before adolescence and lasts for life. The skin lesions are otherwise asymptomatic and do not affect the general health of the patient. The prevalence of DSH was estimated to be ∼1.5 per 100,000 in Japan [1]. DSH has mainly been reported in the Asian population, including Japanese, Chinese, Korean and Indian patients. DSH is known to be caused by mutations in the ADAR gene, also known as ADAR1 or DSRAD, which maps to chromosome 1q21.3 [1]. Recently, genetic mutations of the ADAR gene were reported in Japanese and Chinese patients; however, there has been no mutational analysis in Koreans. A 16-year-old Korean boy had presented asymptomatic, multiple, variable-sized, mottled, hyper- and hypopigmented macules on his extremities and neck since childhood (figure 1A). Besides the patient, four other members of the family were also affected: his father, two male siblings and a nephew. He reported that his late great-grandfather was also affected on his extremities (figure 1B). This study was reviewed and approved by the Institutional Review Board of Uijeongbu St. Mary’s Hospital and both the patient and family gave written informed consent. For genetic analyses, peripheral blood samples were obtained from both affected and non-affected family members of the patient. Mutational analysis of the ADAR gene was performed as previously described [2]. Briefly, genomic DNA was extracted and used as a template for the polymerase chain reaction (PCR) amplification of all 15 exons of the ADAR gene (NM_001111). The sequencing results of affected patients were compared with those of unaffected family members and also with the NCBI reference sequence. A deletion of two bases, c.2433_2434delAG (chr1:154562723 A_154562724 G), was observed in all affected patients. The sequencing results of the PCR products obtained from the proband and his mother, who was unaffected, are shown in figure 1C. The same mutation was also found in other affected members. We speculate that the p.T811fs frameshift mutation (reference NP_001102.2) on exon 7 in the patients in this study led to haploinsufficiency of ADAR enzymatic activity (figure 1D). Adenosine deaminase acting on RNA (ADAR) was identified as the enzyme that catalyzes the conversion of adenosine to inosine in double-stranded RNA substrates, which results in the creation of alternative splicing sites or codon alterations and thus leads to functional changes in the protein. The ADAR gene harbors two Z-alpha domains, three dsRNA-binding domains and a putative deaminase domain (figure 1D). ADAR is expressed ubiquitously throughout the brain, liver, spleen, thymus and peripheral lymphocytes; however, the RNA target of ADAR in the skin remains unknown. Homozygous ADAR knockout mice have been reported to exhibit embryonic lethality; however, heterozygous ADAR mice showed no obvious abnormalities, including in the skin [3]. Two pathological mechanisms for DSH have been proposed. According to the first hypothesis, reduced ADAR activity may occur at extremities distant from the neural crest during the migration of melanoblasts in embryonic development. According to the second hypothesis, reduced ADAR activity causes apoptosis in melanocytes at sites exposed to UV light and secondary hyperpigmentation around hypopigmented
693
B
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D
type 3 (PAX3), type 4A (EDNRB), type 4B (EDN3) and type 4C (SOX10) [10]. Taibjee et al. summarized cases of PM in relationship with chromosomal abnormalities and co-localizing genes, including PAX3, SLUG, EDNRB, EDN3, and SOX10 [5]. In our case, a somatic mutation or epigenetic alteration might have occurred during developing pathways of mesodermal and/or ectodermal derivatives in the chromosomal regions containing a gene associated with auditory-pigmentary abnormalities. Clinical features of the serrated and irregular shapes represent overlapping of ND in our case of PM of the hypopigmented type. Thus, it seems reasonable to categorize ND as skin-limited hypopigmented PM. Disclosure. Financial support: none. Conflict of interest: none.
Figure 1. Clinical pictures of A, B) linear and patchy hypopigmented macules along Blaschko’s lines with serrated and irregular borders on the right side of the neck to the upper chest (arrows), C) the right nape to the upper back (bold arrows) and left nape (arrow). D) The left side of the neck had normal color.
The definite diagnosis for hypopigmented PM is based on non-hereditary cutaneous hypopigmented linear streaks or patches involving more than two body segments and one or more nervous or musculoskeletal anomalies [2]. Nevus depigmentosus (ND) consists of a hypopigmented area distributed as an isolated patch, a unilateral band or a streak, or multiple whorls or streaks [6-8]. The type of multiple whorls or streaks is usually limited in cases without extracutaneous anomalies. ND is usually circumscribed with serrated and irregular shapes, while hypopigmented PM commonly presents straight or circular borders. The diagnostic criteria for HI (hypopigmented PM) proposed by Ruiz-Maldonado et al. are still applicable, because the presence of one or more nervous or musculoskeletal anomalies is required [2]. In the present case, the serrated and irregular shapes mimicked ND but the diagnosis of hypopigmented PM was based on the bilateral hypopigmented lesions associated with congenital sensorineural hearing loss. The auditory brain stem response is useful to confirm congenital sensorineural hearing loss. Ruiz-Maldonado et al. summarized 41 cases of hypopigmented PM and characterized them as linear lesions along Blaschko’s lines in 26, patchy lesions in 9, and patchy and linear lesions in 6 cases [2]. Patchy lesions in PM of the hypopigmented type tend to have squared or rounded rather than linear distribution [2]. To our knowledge, no cases of ND with hearing loss have been reported. Coexistence of cutaneous and nervous system abnormalities suggests the occurrence of a somatic mutation or epigenetic alteration. Our recent survey showed that PM (reported as HI) was present in 1% of all hypopigmented disorders in Japan and ND in 6% [9]. The relatively high frequency of PM and ND was associated with the existence of many pigmentation-associated genes. Blaschko’s lines seem to depict pathways of mesodermal and/or ectodermal derivatives. Segmental distribution reflects mosaicism affecting mesodermal derivatives. Differential diagnoses include auditory-pigmentary abnormalities of Waardenburg syndrome type 1 (caused by a mutation in PAX3), type 2A (MITF), type 2D (SLUG (SNAI2)), type 2E (SOX10), EJD, vol. 24, n◦ 6, November-December 2014
Department of Dermatology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan
Naoki OISO Akira KAWADA
1. Ito M. Studies on melanin X1. Incontinentia pigmenti achrominans. A singular case of nevus depigmentosus systematicus bilateralis. Tohoku J Exp Med 1952; 55: 57-9. 2. Ruiz-Maldonado R, Toussaint S, Tamayo L, Laterza A, del Castillo V. Hypomelanosis of Ito: diagnostic criteria and report of 41 cases. Pediatr Dermatol 1992; 9: 1-10. 3. Oiso N, Amatsu A, Kawara S, Kawada A. Pigmentary mosaicism with hyperpigmented streaks on the palmoplantar lesion associated with balanced X; autosome translocations t(X; 9)(p11.21; q34.1). J Eur Acad Dermatol Venereol 2009; 23: 359-61. 4. Kuster W, Happle R. ‘Hypomelanosis of Ito’ and mosaicism. In Nordlund JJ, Boissy E, Hearing VJ, King RA, Oetting WS, Ortonne JP, eds. The Pigmentary System: Physiology and Pathophisiology, 2nd edn. Blackwell Publishing Ltd, Oxford, 2006: 636-45. 5. Taibjee SM, Bennett DC, Moss C. Abnormal pigmentation in hypomelanosis of Ito and pigmentary mosaicism: the role of pigmentary genes. Br J Dermatol 2004; 151: 269-82. 6. Xu AE, Huang B, Li YW, Wang P, Shen H. Clinical, histopathological and ultrastructural characteristics of naevus depigmentosus. Clin Exp Dermatol 2008; 33: 400-5. 7. Oiso N, Kawada A. The diagnostic usefulness of dermoscopy for nevus depigmentosus. Eur J Dermatol 2011; 21: 639-40. 8. Oiso N, Nomi N, Fukai K, et al. Nevus depigmentosus with pale skin, yellow-brown hair and a bright brown iris. Eur J Dermatol 2014; 24: 406-7. 9. Oiso N, Suzuki T, Wataya-Kaneda M, et al. Guidelines for the diagnosis and treatment of vitiligo in Japan. J Dermatol 2013; 40: 34454. 10. Oiso N, Fukai K, Kawada A, Suzuki T. Piebaldism. J Dermatol 2013; 40: 330-5. doi:10.1684/ejd.2014.2424
Three cases of elastofibroma with immunohistochemical analysis of microfibrillar components Elastofibroma is a rare benign tumor, localized, in most cases, to the infrascapular region [1, 2]. Elastin-specific
691
staining reveals multiple globular or bead-like structures in cross sections [1, 2]. Electron microscopy reveals abnormal flower-like aggregates of elastic fibers, with a central core of elastin surrounded by radiating “petals” of granular and filamentous material, suggesting that the structure and organization of the microfibrils are abnormal [3]. We discuss here three cases of elastofibroma with immunohistochemical analysis of microfibrillar components. Fibulin 2-, 3- and 5- and hemicentin-specific antibodies reacted positively with bead-like structures. Antibodies against latent TGF-binding proteins (LTBPs)1 and -2 also reacted with these structures. Case 1 In January 2007, a 74-year-old female presented for skin cancer screening complaining of a symptomless and slowly growing mass on her left shoulder that she had first noticed two years previously. The tumor was hard and elastic (figure 1A). Magnetic resonance imaging (MRI) revealed a lesion, between the latissimus dorsi muscle and the thoracic-rib infrascapular region, of 70 × 22 × 72 mm. Signal intensity resembled that of skeletal muscle, with regions of alternating high and low signal intensities on T1 and T2 weighted spin-echo sequences, and was typical of elastofibroma. A biopsy specimen contained globular or bead-like structures that stained positively with elas-
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(B)
(C)
(D)
(E)
(F)
(G)
(H)
(I)
(J)
(K)
(L)
(M)
(N)
(O)
Figure 1. Elastic hard, poorly circumscribed tumor around the left scapular area (A). Elastica van Gieson staining (B-D) and immunohistochemical analysis with microfibril-specific antibodies against fibulin-1 (E), -2 (F) -3 (G), -4 (H) and -5 (I); hemicentin (J); LTBP-1 (K), -2 (L), -3 (M) and -4 (N); and fibronectin (O). Original magnification × 40 (B), ×100 (C), ×400 (D-O).
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tica van Gieson stain (figures 1B-D). After a diagnosis of elastofibroma, the tumor was resected surgically. Case 2 A 74-year-old female presented with a painful and slowly growing mass on her left shoulder in March 2008. MRI revealed a lesion between the latissimus dorsi muscle and the thoracic-rib infrascapular area of 60 × 20 × 60 mm. The imaging features resembled those in case 1. After biopsy and a diagnosis of elastofibroma, the tumor was resected surgically in May 2008. Case 3 A 64-year-old male presented with a slowly growing mass on each shoulder that he had noticed for one or two years. MRI revealed a right-side lesion of 83 × 33 mm and a left-side lesion of 73 × 25 mm. After a diagnosis of elastofibroma, both tumors were resected surgically in January 2011. To identify the microfibrillar components that might contribute to the formation of elastofibroma, we performed immunohistochemical staining with microfibrillar component-specific antibodies [4, 5]. In contrast to antibodies against fibulins 1 and 4, antibodies against fibulins 2, 3 and 5 and hemicentin reacted positively with bead-like structures (figures 1E-J). Antibodies against latent TGFbinding proteins (LTBPs)-1 and 2, but not against LTBP-3 and -4, reacted with globular structures (figures 1K-N). Fibronectin-specific antibodies did not react with bead-like structures (figure 1O). To examine whether aging might be important in the formation of elastofibromas, we performed immunohistochemical staining with antibodies against a Dbeta-Asp containing peptide [6]. No staining with these antibodies was detected in elastic structures in resected specimens (data not shown). We detected at least four members of the fibulin family and two kinds of LTBP in our elastofibromas. Elastofibroma often occurs in farmers and manual laborers. Moreover shear stress has been reported to induce activation of TGF1 via LTBP-1, and TGF1 might contribute to the formation and enlargement of this tumor. LTBP-2, which does not bind TGF, might be an indirect negative modulator of storage of the large latent TGF1 complex. The deposition of LTBP within microfibrils does not occur in the absence of fibrillin-1 and fibronectin [7]. We failed to detect fibronectin in this study. The function of hemicentin in the dermis is unclear, but hemicentin has been reported in mouse epidermis, hair follicles and sebaceous glands after immunostaining with antibodies against nematode hemicentin [8]. Biologically rare D-aspartyl (D-Asp) residues have been found in proteins of various tissues, including the skin, of elderly humans. Aspartic acid is the most easily racemizable amino acid and D-Asp might be formed by spontaneous racemization in metabolically inactive tissues during chronological aging. Formation of D-Asp is accompanied by isomerization of natural alpha-Asp to the abnormal beta-Asp [9]. D-Beta-Asp can be detected in sun-damaged dermis and one of the sites of its formation is reported to be elastin [10]. In elastofibroma, this reaction might not contribute to aggregation of elastic components. In summary, the bead-like structures in elastofibroma appear to be composed of several fundamental macromolecules, fibulins and LTBPs. The molecular organization of these components and signature abnormalities of this disease including hereditary factor(s) remain to be elucidated. EJD, vol. 24, n◦ 6, November-December 2014
Disclosure. Acknowledgment: The antibodies against LTBP1 was kindly provided by Prof. Heldin (Ludwig Institute for Cancer Research, Sweden). Financial support: none. Conflict of interest: none. 1
Department of Plastic Surgery Department of Dermatology, 3 Department of Matrix Medicine, Faculty of Medicine, Oita University, Hasama, Yufu, 879-5593, Japan 4 Research Reactor Institute, Kyoto University, Osaka, Japan 2
Miyuki UEHARA1 Kaho MATSUDA1 Aiko KATO1 Seiichi SATO1 Fumiaki SHIMIZU1 Miwako OOATARI1 Yoshitaka KAI2 Hiromitsu SHIMADA2 Yutaka HATANO2 Osamu OKAMOTO2 Kazumoto KATAGIRI2 Takako SASAKI3 Noriko FUJII4 Sakuhei FUJIWARA2
1. Jarvi O, Saxen E. Elastofibroma dorse. Acta Pathol Microbiol Scand Suppl 1961; 51(Suppl 144): 83-4. 2. Nagamine N, Nohara Y, Ito E. Elastofibroma in Okinawa. A clinicopathologic study of 170 cases. Cancer 1982; 50: 1794-805. 3. Kahn HJ, Hanna WM. “Aberrant elastic” in elastofibroma: an immunohistochemical and ultrastructural study. Ultrastruct Pathol 1995; 19: 45-50. 4. Giltay R, Timpl R, Kostka G. Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4. Matrix Biol 1999; 18: 469-80. 5. Kadoya K, Sasaki T, Kostka G, et al. Fibulin-5 deposition in human skin: decrease with ageing and ultraviolet B exposure and increase in solar elastosis. Br J Dermatol 2005; 153: 607-12. 6. Motoie R, Fujii N, Tsunoda S, et al. Localization of D-bAspartyl Residue-Containing Proteins in Various Tissues. Int J Mol Sci 2009; 10: 1999-2009. 7. Baldwin AK, Simpson A, Steer R, et al. Elastic fibres in health and disease. Expert Rev Mol Med 2013; 15: e8. doi: 10.1017/erm.2013.9. 8. Xu X, Dong C, Vogel BE. Hemicentins assemble on diverse epithelia in the mouse. J Histochem Cytochem 2007; 55: 119-26. 9. Fujii N, Harada K, Momose Y, et al. D-amino acid formation induced by a chiral field within a human lens protein during aging. Biophys Biochem Res Commun 1999; 263: 322-6. 10. Fujii N, Tajima S, Tanaka N, et al. The presence of D-beta-aspartic acid-containing peptides in elastic fibers of sun-damaged skin: A potent marker for ultraviolet-induced skin aging. Biochem Biophys Res Comm 2002; 294: 1047-51. doi:10.1684/ejd.2014.2427
A frameshift mutation in the ADAR gene in a Korean family with dyschromatosis symmetrica hereditaria Dyschromatosis symmetrica hereditaria (DSH; MIM 127400) is a rare autosomal dominant skin disorder characterized by a mixture of hyper- and hypopigmented macules on the dorsal surface of the extremities and face. Onset of the disease is usually during infancy or early childhood. EJD, vol. 24, n◦ 6, November-December 2014
Dyschromatosis stops spreading before adolescence and lasts for life. The skin lesions are otherwise asymptomatic and do not affect the general health of the patient. The prevalence of DSH was estimated to be ∼1.5 per 100,000 in Japan [1]. DSH has mainly been reported in the Asian population, including Japanese, Chinese, Korean and Indian patients. DSH is known to be caused by mutations in the ADAR gene, also known as ADAR1 or DSRAD, which maps to chromosome 1q21.3 [1]. Recently, genetic mutations of the ADAR gene were reported in Japanese and Chinese patients; however, there has been no mutational analysis in Koreans. A 16-year-old Korean boy had presented asymptomatic, multiple, variable-sized, mottled, hyper- and hypopigmented macules on his extremities and neck since childhood (figure 1A). Besides the patient, four other members of the family were also affected: his father, two male siblings and a nephew. He reported that his late great-grandfather was also affected on his extremities (figure 1B). This study was reviewed and approved by the Institutional Review Board of Uijeongbu St. Mary’s Hospital and both the patient and family gave written informed consent. For genetic analyses, peripheral blood samples were obtained from both affected and non-affected family members of the patient. Mutational analysis of the ADAR gene was performed as previously described [2]. Briefly, genomic DNA was extracted and used as a template for the polymerase chain reaction (PCR) amplification of all 15 exons of the ADAR gene (NM_001111). The sequencing results of affected patients were compared with those of unaffected family members and also with the NCBI reference sequence. A deletion of two bases, c.2433_2434delAG (chr1:154562723 A_154562724 G), was observed in all affected patients. The sequencing results of the PCR products obtained from the proband and his mother, who was unaffected, are shown in figure 1C. The same mutation was also found in other affected members. We speculate that the p.T811fs frameshift mutation (reference NP_001102.2) on exon 7 in the patients in this study led to haploinsufficiency of ADAR enzymatic activity (figure 1D). Adenosine deaminase acting on RNA (ADAR) was identified as the enzyme that catalyzes the conversion of adenosine to inosine in double-stranded RNA substrates, which results in the creation of alternative splicing sites or codon alterations and thus leads to functional changes in the protein. The ADAR gene harbors two Z-alpha domains, three dsRNA-binding domains and a putative deaminase domain (figure 1D). ADAR is expressed ubiquitously throughout the brain, liver, spleen, thymus and peripheral lymphocytes; however, the RNA target of ADAR in the skin remains unknown. Homozygous ADAR knockout mice have been reported to exhibit embryonic lethality; however, heterozygous ADAR mice showed no obvious abnormalities, including in the skin [3]. Two pathological mechanisms for DSH have been proposed. According to the first hypothesis, reduced ADAR activity may occur at extremities distant from the neural crest during the migration of melanoblasts in embryonic development. According to the second hypothesis, reduced ADAR activity causes apoptosis in melanocytes at sites exposed to UV light and secondary hyperpigmentation around hypopigmented
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