A
B
C
Figure 1. A) Multiple annular erythematous plaques with raised borders disseminated on the lower limbs, B) A close-up view of the lesions. C) Skin biopsy showed compact hyperkeratosis with parakeratotic cells corresponding to the cornoid lamella associated with a thin epidermis where the granular layer is interrupted. (Hematoxylin-eosin stain; magnification: ×20).
The paraneoplastic nature of PK has been reported in the literature in 6 cases of PK associated with solid organ malignancies, including hepatitis C virus-related hepatocellular carcinoma [6], cholangiocarcinoma [3, 4] and ovarian cancer [5] with a simultaneous onset and a parallel course of both pathologies. In the present case, the hypothesis of a paraneoplastic syndrome seems unlikely. Indeed, there is no obvious parallelism since the PK lesions appeared a long time (4 years) before the clinical diagnosis of ovarian cancer and relapsed while the tumor was considered in remission. However, neoplasia may remain silent for several years at an infra clinical stage [7] and it is possible that the ovarian cancer had already relapsed at an infra clinical stage, justifying that the patient is now under strict medical surveillance. The main interesting observation of this case is the complete remission of PK with cancer chemotherapy, which has never been reported in the literature. Cannavó et al described the disappearance of PK lesions in a patient with ovarian cancer treated with carboplatin and paclitaxel but they linked PK healing to the successful treatment of the cancer, finally retaining the diagnosis of paraneoplastic PK [5]. Indeed, a direct effect of chemotherapy on PK lesions can be suspected since: i) carboplatin and paclitaxel block mitosis of cells with a rapid turn-over; ii) the mutant clones of PK are hyperproliferative [1, 2]; iii) overexpression of the p53 gene product has been demonstrated under the cornoid lamella [1, 8]. Moreover, PK lesions may undergo malignant transformation to squamous cell carcinoma (SCC) [1, 2] and these 2 chemotherapy drugs are known to be effective in treating SCC [9]. Disclosure. Financial support: none. Conflict of interest: none. EJD, vol. 24, n◦ 2, March-April 2014
1
Allergology and Clinical Immunology Department, 2 Medical Oncology Department, UMR 3738, 3 Histopathology Laboratory, 4 Allergology and Clinical Immunology Department, INSERM U 1111-CIRI, Lyon-Sud University Hospital, Lyon 1 University, 69495 Pierre-Bénite cedex, France
Anne Laure BRETON1 Pauline PRALONG1 Véronique TRILLET-LENOIR2 Brigitte BALME3 Jean-Franc¸ois NICOLAS4 Frédéric BERARD4
1. Kanitakis J, Euvrard S, Faure M, Claudy A. Porokeratosis and immunosuppression. Eur J Dermatol 1998; 8: 459-65. 2. Marque M, Meunier L. Porokeratosis. Ann Dermatol Venereol 2012; 139: 668-76. 3. Lee H-W, Oh S-H, Choi J-C, et al. Disseminated superficial porokeratosis in a patient with cholangiocarcinoma. J Am Acad Dermatol 2006; 54 (2 Suppl): S56-8. 4. Torres T, Velho GC, Selores M. Disseminated superficial porokeratosis in a patient with cholangiocarcinoma: a paraneoplastic manifestation? An Bras Dermatol 2010; 85: 229-31. 5. Cannavó SP, Borgia F, Adamo B, Guarneri B. Simultaneous development and parallel course of disseminated superficial porokeratosis and ovarian cancer: Coincidental association or true paraneoplastic syndrome? J Am Acad Dermatol 2008; 58: 657-60. 6. Kono T, Kobayashi H, Ishii M, Nishiguchi S, Taniguchi S. Synchronous development of disseminated superficial porokeratosis and hepatitis C virus-related hepatocellular carcinoma. J Am Acad Dermatol 2000; 43(5 Pt 2): 966-8. 7. Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 2001; 357: 96-100. 8. Magee JW, McCalmont TH, LeBoit PE. Overexpression of p53 tumor suppressor protein in porokeratosis. Arch Dermatol 1994; 130: 187-90. 9. Arnold SM, Regine WF, Ahmed MM, et al. Low-dose fractionated radiation as a chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma of the head and neck: results of a new treatment paradigm. Int J Radiat Oncol Biol Phys 2004; 58: 1411-7. doi:10.1684/ejd.2014.2289
Hereditary apolipoprotein A1 amyloidosis with cutaneous and cardiac involvement: a long familial history Amyloidoses are a group of rare diseases characterized by the extracellular deposition of amyloid fibrils in tissues and organs [1]. The kidney, heart, liver and the peripheral nervous system are predominantly involved, whereas the skin is only rarely affected. More than 28 proteins have been identified to date as amyloidogenic, causing either systemic or a localized, sporadic or hereditary disease. Among the hereditary systemic amyloidoses, the number of mutated proteins known to be amyloidogenic is continuously growing. The list presently includes variant forms of transthyretin, gelsolin, fibrinogen A alpha-chain, lysozyme, apolipoprotein AI and AII, cystatin C and 2-microglobulin [2]. Mutations in apolipoprotein-AI
261
(Apo-AI) are of particular interest because they are associated with a wide clinical spectrum including nephropathy, hepatopathy, cardiomyopathy, testicular involvement and occasionally neuropathy. To date, 19 Apo-AI mutations have been identified and a few of them are associated with cutaneous and cardiac localizations [3-5]. A 32 year-old woman was referred for a 3-year history of sparse yellowish plaques on her face, resulting from the confluence of multiple small papules (figures 1A-B). The evaluation of hematochemical parameters was unremarkable. A skin biopsy revealed the presence of amorphous, eosinophilic material in the papillary dermis (figure 1C), which showed apple-green birefringence after Congo red staining under polarized light, the hallmark of amyloid deposits. Immunostaining with an anti-cytokeratin antibody (MNF116, Dako) was negative, excluding primary cutaneous amyloidosis. After the biopsy results were available, the patient mentioned that her father suffered from cardiac amyloidosis, associated with the Leu174Ser variant of Apo-AI [5], and was awaiting heart transplantation. DNA analysis confirmed that she was heterozygous for the same mutation as her father. Ultrastructural examination showed amyloid fibrils in the dermis, which were immunostained with a polyclonal rabbit anti-human Apo-AI antibody (Q 0496, Dako) (figure 1D). Cardiac imagining ruled out concomitant cardiac involvement. Surprisingly, the father’s medical history revealed that, 15 years previously, he had been evaluated in our institute for a progressive dermatosis of the hands and face, which at that time was diagnosed as “papulo-verrucous colloid milium” and was described in a previous publication [6]. In 2000, a skin biopsy of the forehead had revealed a thinned epidermis with subepidermal deposits of an amorphous, weakly eosinophilic material. A hyperplastic epidermis, with the presence of the same amorphous material in the dermis, was also observed in the dorsum of the hand. The histochemical examination was negative for PAS and was not
birefringent after Congo red staining, thus ruling out cutaneous amyloidosis. Professional contact with lubricating oils and the outdoor exposure of the propositus led us to the diagnosis of a professional form of “papuloverrucous colloid milium”. We retrospectively re-reviewed the father’s biopsy specimens and the correct diagnosis of cutaneous amyloidosis was finally established. The lessons we learnt from this familial story highlight possible pitfalls in diagnosing amyloidosis. The results of Congo red staining may sometimes be ambiguous and in this respect multiple sampling, correct staining protocols, long-observation, a good polarizer and room darkness are important to overcome the low sensitivity due to the presence of scanty and unevenly-distributed amyloid deposits [7]. The skin is a difficult tissue to evaluate for amyloid deposits after Congo red staining, due to the presence of bundles of collagen fibers that show non-specific birefringence. Electron microscopy can confirm or rule out the diagnosis of amyloidosis and can detect even scant deposits of amyloid fibrils in organs and tissues, including the skin [8, 9]. Furthermore, immunoelectron-microscopy has been largely validated as correctly characterizing the amyloid proteins [9]. More recently, proteomic-based methodologies have proved highly sensitive and concordant with immunoelectron microscopy in amyloid typing [10]. In conclusion, the diagnosis of cutaneous amyloidosis always requires histochemical demonstration of amyloid deposits in tissue sections and definite typing of the constitutive protein. Advanced techniques may complement Congo red staining to confirm or exclude the diagnosis in doubtful cases. Genetic testing is mandatory to ultimately establish the diagnosis of hereditary amyloidosis. For the dermatologist, it is important to know that cutaneous involvement may be an early symptom which can precede systemic involvement in the rare cases of hereditary amyloidosis. Disclosure. Financial support: none. Conflict of interest: none.
A
B 1
Dermatopathology Laboratory, Dermatology Department, Ifo-San Gallicano Institute, Via Chianesi 53, 00144 Roma, Italy 3 Department of Pathology, 4 Amyloidosis Research and Treatment Center, Fondazione-IRCCS Policlinico San Matteo and University of Pavia, Italy 2
C
D
Figure 1. A, B) yellowish plaques on the patient’s face. C) Amorphous eosinophilic material in the papillary dermis. D) Amyloid fibrils in the dermis, labelled with a polyclonal gold-conjugated anti-apolipoprotein A-1 antibody (electronmicroscopic examination).
262
Luca MUSCARDIN1 Carlo COTA1 Pietro DONATI1 Jo Linda SINAGRA2 Marco PAULLI3 Giampaolo MERLINI4 Laura VERGA3 Laura OBICI4 Gian Luca CAPELLO3
1. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. New Engl J Med 2003; 349: 583-96. 2. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 2012; 19: 167-70. 3. Moulin G. Amylose disséminée familiale à prédominance cutanée et cardiaque par mutation de l’apolipoprotéine A1. Ann Dermatol Venereol 2000; 127: 745-8. EJD, vol. 24, n◦ 2, March-April 2014
4. Rowczenio D, Dogan A, Theis JD, et al. Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I. Am J Pathol 2011; 179: 1978-87. 5. Obici L, Bellotti V, Mangione P, et al. The new apolipoprotein AI variant Leu174Ser causes hereditary cardiac amyloidosis and the amyloid fibrils are constituted of the 93 residues N-terminal polypeptide. Am J Pathol 1999; 155: 695-702. 6. Muscardin L, Bellocci M, Balus L. Papuloverrucous colloid milium: an occupational variant. Br J Dermatol 2000; 143: 1-5. 7. Picken MM. Amyloidosis - where are we now and where are we heading? Arch Pathol Lab Med 2010; 134: 545-51. 8. Guenova E, Schaller M. Dermatological indications for electron microscopy. Amyloid depositions. Eur J Dermatol 2012; 22: 295. 9. Verga L, Morbini P, Palladini G, et al. Amyloid typing: immunoelectron microscopy. In: Picken MM, Dogan A, Herrera GA (eds) - Amyloid and Related Disorders, Surgical Pathology and Clinical Correlations. Humana Press, Springer Science-Business Media, 2012. 10. Brambilla F, Lavatelli F, Di Silvestre V, et al. Reliable typing of systemic amyloidoses through proteomic analysis of subcutaneous adipose tissue. Blood 2012; 119: 1844-7. doi:10.1684/ejd.2014.2287
Hailey-Hailey disease diagnosed based on an exacerbation of contact dermatitis with topical crotamiton Hailey-Hailey disease (HHD; OMIM #169600), also known as benign familial chronic pemphigus, is a rare hereditary condition characterized by the formation of blisters at sites of friction. HHD is caused by mutations in the ATP2C1 gene. We herein describe a patient with HHD who was diagnosed following the exacerbation of skin lesions resulting from contact dermatitis induced by crotamiton. A 67-year-old female was admitted with complaints of itchy eruptions on the right sole, groin and trunk. She had a 20-year history of recurrent scaly erythema and erosion in intertriginous regions, especially on the axillae and groin. The skin lesions usually worsened during the summer; however, she did not consult a doctor. Due to the development of areas of itchy eruption on the right sole two weeks prior to admission, she had applied an over-the-counter antifungal agent, Lamisil plus cream® , externally on the affected site. The skin at the application site subsequently worsened. A physical examination revealed erythema with yellow crusts on the right sole and scaly erythema on the abdomen, axillae and groin (figures 1A-C). Direct microscopic observation and a mycology culture of the lesions showed no fungus. A skin biopsy of both the groin and right sole revealed suprabasal acantholysis, thus suggesting HHD (figures 1D-F). A patch test was performed with the components of Lamisil plus cream® , terbinafine hydrochloride 0.1%, 1% and 10% pet, crotamiton 0.1%, 1%, 10% pet and pure, glycyrrhizic acid 0.1%, 1% and 10% pet, I-menthol 0.1%, 1% and 10% pet and urea 0.1%, 1% and 10% pet according to the protocol of the International Contact Dermatitis Research Group (ICDRG). A positive reaction was observed for crotamiton only at 48 and 72 hours. The other ingredients did not show any positive reactions. Because the histological findings suggested a diagnosis of HHD, we performed a mutation analysis of the ATP2C1 gene in a peripheral blood sample. As a result, a heterozygous EJD, vol. 24, n◦ 2, March-April 2014
missense mutation (c. 457C>T) was identified in exon 7 of the ATP2C1 gene, resulting in a nonsense mutation p. Arg153X. This mutation has been previously reported [1]. Based on these findings, the patient was diagnosed with HHD. She had no relevant family history. She was instructed to avoid the topical application of crotamiton and prevent friction of the skin. Subsequently, she reported relief of her condition after two years of follow-up. Factors exacerbating HHD include a high temperature, high humidity, hyperhidrosis, skin friction, bacterial infection, mycotic infection, etc. In addition, contact dermatitis is known to be a factor of disease exacerbation. To date, a few HHD cases have been reported in which the disease was exacerbated by contact dermatitis resulting from topical ointments [2-4]. Izumi et al. reported an HHD patient in whom the skin lesions were generalized due to contact dermatitis caused by topical neomycin [4]. Pónyai et al. reported two HHD patients who were triggered by contact sensitivity [3]. One of them was induced by a cream containing methylchloroisothiazolinone/methylisothiazolinone, while the other was induced by a deodorant. In these patients, patch tests showed positive reactions for causative ingredients, while histopathology demonstrated suprabasal acantholysis, compatible with the findings of HHD [2, 3]. In the present case, contact dermatitis induced by crotamiton led to the diagnosis of HHD. To our best knowledge,
A
D
200nm
B
E
C
F
200nm
100nm
Figure 1. Clinical and histological findings. Scaly erythema on the abdomen A) and groin B). C) Yellow crusts, erythema and areas of erosion on the right sole. D) Groin: suprabasal acantholysis with vesicle formation in the epidermis and perivascular lymphocytes infiltrating the upper dermis (Hematoxylin-Eosin staining; original magnification ×10). E) Right sole: acantholysis, mild spongiosis and lymphocyte exocytosis in the epidermis (Hematoxylin-Eosin staining; original magnification ×10). F) Right sole: in the areas of acantholysis, there were no dyskeratotic cells, especially corps ronds and grains (Hematoxylin-Eosin staining; original magnification ×20).
263
B
C
Figure 1. A) Multiple annular erythematous plaques with raised borders disseminated on the lower limbs, B) A close-up view of the lesions. C) Skin biopsy showed compact hyperkeratosis with parakeratotic cells corresponding to the cornoid lamella associated with a thin epidermis where the granular layer is interrupted. (Hematoxylin-eosin stain; magnification: ×20).
The paraneoplastic nature of PK has been reported in the literature in 6 cases of PK associated with solid organ malignancies, including hepatitis C virus-related hepatocellular carcinoma [6], cholangiocarcinoma [3, 4] and ovarian cancer [5] with a simultaneous onset and a parallel course of both pathologies. In the present case, the hypothesis of a paraneoplastic syndrome seems unlikely. Indeed, there is no obvious parallelism since the PK lesions appeared a long time (4 years) before the clinical diagnosis of ovarian cancer and relapsed while the tumor was considered in remission. However, neoplasia may remain silent for several years at an infra clinical stage [7] and it is possible that the ovarian cancer had already relapsed at an infra clinical stage, justifying that the patient is now under strict medical surveillance. The main interesting observation of this case is the complete remission of PK with cancer chemotherapy, which has never been reported in the literature. Cannavó et al described the disappearance of PK lesions in a patient with ovarian cancer treated with carboplatin and paclitaxel but they linked PK healing to the successful treatment of the cancer, finally retaining the diagnosis of paraneoplastic PK [5]. Indeed, a direct effect of chemotherapy on PK lesions can be suspected since: i) carboplatin and paclitaxel block mitosis of cells with a rapid turn-over; ii) the mutant clones of PK are hyperproliferative [1, 2]; iii) overexpression of the p53 gene product has been demonstrated under the cornoid lamella [1, 8]. Moreover, PK lesions may undergo malignant transformation to squamous cell carcinoma (SCC) [1, 2] and these 2 chemotherapy drugs are known to be effective in treating SCC [9]. Disclosure. Financial support: none. Conflict of interest: none. EJD, vol. 24, n◦ 2, March-April 2014
1
Allergology and Clinical Immunology Department, 2 Medical Oncology Department, UMR 3738, 3 Histopathology Laboratory, 4 Allergology and Clinical Immunology Department, INSERM U 1111-CIRI, Lyon-Sud University Hospital, Lyon 1 University, 69495 Pierre-Bénite cedex, France
Anne Laure BRETON1 Pauline PRALONG1 Véronique TRILLET-LENOIR2 Brigitte BALME3 Jean-Franc¸ois NICOLAS4 Frédéric BERARD4
1. Kanitakis J, Euvrard S, Faure M, Claudy A. Porokeratosis and immunosuppression. Eur J Dermatol 1998; 8: 459-65. 2. Marque M, Meunier L. Porokeratosis. Ann Dermatol Venereol 2012; 139: 668-76. 3. Lee H-W, Oh S-H, Choi J-C, et al. Disseminated superficial porokeratosis in a patient with cholangiocarcinoma. J Am Acad Dermatol 2006; 54 (2 Suppl): S56-8. 4. Torres T, Velho GC, Selores M. Disseminated superficial porokeratosis in a patient with cholangiocarcinoma: a paraneoplastic manifestation? An Bras Dermatol 2010; 85: 229-31. 5. Cannavó SP, Borgia F, Adamo B, Guarneri B. Simultaneous development and parallel course of disseminated superficial porokeratosis and ovarian cancer: Coincidental association or true paraneoplastic syndrome? J Am Acad Dermatol 2008; 58: 657-60. 6. Kono T, Kobayashi H, Ishii M, Nishiguchi S, Taniguchi S. Synchronous development of disseminated superficial porokeratosis and hepatitis C virus-related hepatocellular carcinoma. J Am Acad Dermatol 2000; 43(5 Pt 2): 966-8. 7. Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 2001; 357: 96-100. 8. Magee JW, McCalmont TH, LeBoit PE. Overexpression of p53 tumor suppressor protein in porokeratosis. Arch Dermatol 1994; 130: 187-90. 9. Arnold SM, Regine WF, Ahmed MM, et al. Low-dose fractionated radiation as a chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma of the head and neck: results of a new treatment paradigm. Int J Radiat Oncol Biol Phys 2004; 58: 1411-7. doi:10.1684/ejd.2014.2289
Hereditary apolipoprotein A1 amyloidosis with cutaneous and cardiac involvement: a long familial history Amyloidoses are a group of rare diseases characterized by the extracellular deposition of amyloid fibrils in tissues and organs [1]. The kidney, heart, liver and the peripheral nervous system are predominantly involved, whereas the skin is only rarely affected. More than 28 proteins have been identified to date as amyloidogenic, causing either systemic or a localized, sporadic or hereditary disease. Among the hereditary systemic amyloidoses, the number of mutated proteins known to be amyloidogenic is continuously growing. The list presently includes variant forms of transthyretin, gelsolin, fibrinogen A alpha-chain, lysozyme, apolipoprotein AI and AII, cystatin C and 2-microglobulin [2]. Mutations in apolipoprotein-AI
261
(Apo-AI) are of particular interest because they are associated with a wide clinical spectrum including nephropathy, hepatopathy, cardiomyopathy, testicular involvement and occasionally neuropathy. To date, 19 Apo-AI mutations have been identified and a few of them are associated with cutaneous and cardiac localizations [3-5]. A 32 year-old woman was referred for a 3-year history of sparse yellowish plaques on her face, resulting from the confluence of multiple small papules (figures 1A-B). The evaluation of hematochemical parameters was unremarkable. A skin biopsy revealed the presence of amorphous, eosinophilic material in the papillary dermis (figure 1C), which showed apple-green birefringence after Congo red staining under polarized light, the hallmark of amyloid deposits. Immunostaining with an anti-cytokeratin antibody (MNF116, Dako) was negative, excluding primary cutaneous amyloidosis. After the biopsy results were available, the patient mentioned that her father suffered from cardiac amyloidosis, associated with the Leu174Ser variant of Apo-AI [5], and was awaiting heart transplantation. DNA analysis confirmed that she was heterozygous for the same mutation as her father. Ultrastructural examination showed amyloid fibrils in the dermis, which were immunostained with a polyclonal rabbit anti-human Apo-AI antibody (Q 0496, Dako) (figure 1D). Cardiac imagining ruled out concomitant cardiac involvement. Surprisingly, the father’s medical history revealed that, 15 years previously, he had been evaluated in our institute for a progressive dermatosis of the hands and face, which at that time was diagnosed as “papulo-verrucous colloid milium” and was described in a previous publication [6]. In 2000, a skin biopsy of the forehead had revealed a thinned epidermis with subepidermal deposits of an amorphous, weakly eosinophilic material. A hyperplastic epidermis, with the presence of the same amorphous material in the dermis, was also observed in the dorsum of the hand. The histochemical examination was negative for PAS and was not
birefringent after Congo red staining, thus ruling out cutaneous amyloidosis. Professional contact with lubricating oils and the outdoor exposure of the propositus led us to the diagnosis of a professional form of “papuloverrucous colloid milium”. We retrospectively re-reviewed the father’s biopsy specimens and the correct diagnosis of cutaneous amyloidosis was finally established. The lessons we learnt from this familial story highlight possible pitfalls in diagnosing amyloidosis. The results of Congo red staining may sometimes be ambiguous and in this respect multiple sampling, correct staining protocols, long-observation, a good polarizer and room darkness are important to overcome the low sensitivity due to the presence of scanty and unevenly-distributed amyloid deposits [7]. The skin is a difficult tissue to evaluate for amyloid deposits after Congo red staining, due to the presence of bundles of collagen fibers that show non-specific birefringence. Electron microscopy can confirm or rule out the diagnosis of amyloidosis and can detect even scant deposits of amyloid fibrils in organs and tissues, including the skin [8, 9]. Furthermore, immunoelectron-microscopy has been largely validated as correctly characterizing the amyloid proteins [9]. More recently, proteomic-based methodologies have proved highly sensitive and concordant with immunoelectron microscopy in amyloid typing [10]. In conclusion, the diagnosis of cutaneous amyloidosis always requires histochemical demonstration of amyloid deposits in tissue sections and definite typing of the constitutive protein. Advanced techniques may complement Congo red staining to confirm or exclude the diagnosis in doubtful cases. Genetic testing is mandatory to ultimately establish the diagnosis of hereditary amyloidosis. For the dermatologist, it is important to know that cutaneous involvement may be an early symptom which can precede systemic involvement in the rare cases of hereditary amyloidosis. Disclosure. Financial support: none. Conflict of interest: none.
A
B 1
Dermatopathology Laboratory, Dermatology Department, Ifo-San Gallicano Institute, Via Chianesi 53, 00144 Roma, Italy 3 Department of Pathology, 4 Amyloidosis Research and Treatment Center, Fondazione-IRCCS Policlinico San Matteo and University of Pavia, Italy 2
C
D
Figure 1. A, B) yellowish plaques on the patient’s face. C) Amorphous eosinophilic material in the papillary dermis. D) Amyloid fibrils in the dermis, labelled with a polyclonal gold-conjugated anti-apolipoprotein A-1 antibody (electronmicroscopic examination).
262
Luca MUSCARDIN1 Carlo COTA1 Pietro DONATI1 Jo Linda SINAGRA2 Marco PAULLI3 Giampaolo MERLINI4 Laura VERGA3 Laura OBICI4 Gian Luca CAPELLO3
1. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. New Engl J Med 2003; 349: 583-96. 2. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 2012; 19: 167-70. 3. Moulin G. Amylose disséminée familiale à prédominance cutanée et cardiaque par mutation de l’apolipoprotéine A1. Ann Dermatol Venereol 2000; 127: 745-8. EJD, vol. 24, n◦ 2, March-April 2014
4. Rowczenio D, Dogan A, Theis JD, et al. Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I. Am J Pathol 2011; 179: 1978-87. 5. Obici L, Bellotti V, Mangione P, et al. The new apolipoprotein AI variant Leu174Ser causes hereditary cardiac amyloidosis and the amyloid fibrils are constituted of the 93 residues N-terminal polypeptide. Am J Pathol 1999; 155: 695-702. 6. Muscardin L, Bellocci M, Balus L. Papuloverrucous colloid milium: an occupational variant. Br J Dermatol 2000; 143: 1-5. 7. Picken MM. Amyloidosis - where are we now and where are we heading? Arch Pathol Lab Med 2010; 134: 545-51. 8. Guenova E, Schaller M. Dermatological indications for electron microscopy. Amyloid depositions. Eur J Dermatol 2012; 22: 295. 9. Verga L, Morbini P, Palladini G, et al. Amyloid typing: immunoelectron microscopy. In: Picken MM, Dogan A, Herrera GA (eds) - Amyloid and Related Disorders, Surgical Pathology and Clinical Correlations. Humana Press, Springer Science-Business Media, 2012. 10. Brambilla F, Lavatelli F, Di Silvestre V, et al. Reliable typing of systemic amyloidoses through proteomic analysis of subcutaneous adipose tissue. Blood 2012; 119: 1844-7. doi:10.1684/ejd.2014.2287
Hailey-Hailey disease diagnosed based on an exacerbation of contact dermatitis with topical crotamiton Hailey-Hailey disease (HHD; OMIM #169600), also known as benign familial chronic pemphigus, is a rare hereditary condition characterized by the formation of blisters at sites of friction. HHD is caused by mutations in the ATP2C1 gene. We herein describe a patient with HHD who was diagnosed following the exacerbation of skin lesions resulting from contact dermatitis induced by crotamiton. A 67-year-old female was admitted with complaints of itchy eruptions on the right sole, groin and trunk. She had a 20-year history of recurrent scaly erythema and erosion in intertriginous regions, especially on the axillae and groin. The skin lesions usually worsened during the summer; however, she did not consult a doctor. Due to the development of areas of itchy eruption on the right sole two weeks prior to admission, she had applied an over-the-counter antifungal agent, Lamisil plus cream® , externally on the affected site. The skin at the application site subsequently worsened. A physical examination revealed erythema with yellow crusts on the right sole and scaly erythema on the abdomen, axillae and groin (figures 1A-C). Direct microscopic observation and a mycology culture of the lesions showed no fungus. A skin biopsy of both the groin and right sole revealed suprabasal acantholysis, thus suggesting HHD (figures 1D-F). A patch test was performed with the components of Lamisil plus cream® , terbinafine hydrochloride 0.1%, 1% and 10% pet, crotamiton 0.1%, 1%, 10% pet and pure, glycyrrhizic acid 0.1%, 1% and 10% pet, I-menthol 0.1%, 1% and 10% pet and urea 0.1%, 1% and 10% pet according to the protocol of the International Contact Dermatitis Research Group (ICDRG). A positive reaction was observed for crotamiton only at 48 and 72 hours. The other ingredients did not show any positive reactions. Because the histological findings suggested a diagnosis of HHD, we performed a mutation analysis of the ATP2C1 gene in a peripheral blood sample. As a result, a heterozygous EJD, vol. 24, n◦ 2, March-April 2014
missense mutation (c. 457C>T) was identified in exon 7 of the ATP2C1 gene, resulting in a nonsense mutation p. Arg153X. This mutation has been previously reported [1]. Based on these findings, the patient was diagnosed with HHD. She had no relevant family history. She was instructed to avoid the topical application of crotamiton and prevent friction of the skin. Subsequently, she reported relief of her condition after two years of follow-up. Factors exacerbating HHD include a high temperature, high humidity, hyperhidrosis, skin friction, bacterial infection, mycotic infection, etc. In addition, contact dermatitis is known to be a factor of disease exacerbation. To date, a few HHD cases have been reported in which the disease was exacerbated by contact dermatitis resulting from topical ointments [2-4]. Izumi et al. reported an HHD patient in whom the skin lesions were generalized due to contact dermatitis caused by topical neomycin [4]. Pónyai et al. reported two HHD patients who were triggered by contact sensitivity [3]. One of them was induced by a cream containing methylchloroisothiazolinone/methylisothiazolinone, while the other was induced by a deodorant. In these patients, patch tests showed positive reactions for causative ingredients, while histopathology demonstrated suprabasal acantholysis, compatible with the findings of HHD [2, 3]. In the present case, contact dermatitis induced by crotamiton led to the diagnosis of HHD. To our best knowledge,
A
D
200nm
B
E
C
F
200nm
100nm
Figure 1. Clinical and histological findings. Scaly erythema on the abdomen A) and groin B). C) Yellow crusts, erythema and areas of erosion on the right sole. D) Groin: suprabasal acantholysis with vesicle formation in the epidermis and perivascular lymphocytes infiltrating the upper dermis (Hematoxylin-Eosin staining; original magnification ×10). E) Right sole: acantholysis, mild spongiosis and lymphocyte exocytosis in the epidermis (Hematoxylin-Eosin staining; original magnification ×10). F) Right sole: in the areas of acantholysis, there were no dyskeratotic cells, especially corps ronds and grains (Hematoxylin-Eosin staining; original magnification ×20).
263
