reduced in the lymphoblastoid cell-line from a patient with the mutation m.7445A>G [7]. Despite these findings, it remains unknown how the mutation actually causes PPK and deafness. Nevertheless, because of the large clinical overlaps between patients with the connexin-gene mutations and the mitochondrial mutation, we hypothesize that decreased expression of tRNASer (UCN) might result in an aberrant expression of connexins. Further studies need to be performed to disclose the underlying pathomechanisms. It is worth noting that all the affected individuals in our family showed not only PPK and deafness but also nail dystrophy (figures 1D-E; data not shown). In particular, the toe nails looked rather hypoplastic (figure 1D). To our knowledge, nail anomalies in patients with the mutation m.7445A>G have not previously been reported, thus our findings will provide precious information to better understand the phenotypes resulting from the mitochondrial mutation. Disclosure. Financial support: This study was supported in part by “Research on Measures for Intractable Diseases” Project: matching fund subsidy (H26-077) from Ministry of Health, Labour, and Welfare, Japan. Conflict of interest: none. 1
Division of Dermatology, Laboratory of Genetic Skin Diseases, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan 3 Morishita Dermatology Clinic, Nagaoka, Japan 2
Ryota HAYASHI1,2 Hiroshi FUJIWARA1 Michiko MORISHITA3 Masaaki ITO1 Yutaka SHIMOMURA2
1. de Zwart-Storm EA, Hamm H, Stoevesandt J, et al. A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness. J Med Genet 2008; 45: 161-6. 2. Richard G, Rouan F, Willoughby CE, et al. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitisichthyosis-deafness syndrome. Am J Hum Genet 2002; 70: 1341-8. 3. Richard G, Brown N, Ishida-Yamamoto A, Krol A. Expanding the phenotypic spectrum of Cx26 disorders: Bart-Pumphrey syndrome is caused by a novel missense mutation in GJB2. J Invest Dermatol 2004; 123: 856-63. 4. Jan AY, Amin S, Ratajczak P, Richard G, Sybert VP. Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. J Invest Dermatol 2004; 122: 1108-13. 5. Sevior KB, Hatamochi A, Stewart IA, et al. Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness. Am J Med Genet 1998; 75: 179-85. 6. Smith FJ, Morley SM, McLean WH. A novel connexin 30 mutation in Clouston syndrome. J Invest Dermatol 2002; 118: 530-2. 7. Reid FM, Rovio A, Holt IJ, Jacobs HT. Molecular phenotype of a human lymphoblastoid cell-line homoplasmic for the np 7445 deafnessassociated mitochondrial mutation. Hum Mol Genet 1997; 6: 443-9. 8. Reid FM, Vernham GA, Jacobs HT. A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum Mut 1994; 3: 243-7. 9. Martin L, Toutain A, Guillen C, et al. Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome. Br J Dermatol 2000; 143: 87683. EJD, vol. 25, n◦ 1, January-February 2015
10. Caria H, Matos S, Oliveira-Soares R, et al. A7445G mtDNA mutation present in a Portuguese family exhibiting hereditary deafness and palmoplantar keratoderma. J Eur Acad Dermatol Venereol 2005; 19: 455-8. doi:10.1684/ejd.2014.2461
Blepharoconjunctivitis and an unusual location of metastatic breast carcinoma Eyelid metastases represent less than 1% of malignant eyelid lesions. We report a case of single right-eyelid infiltration, which revealed metastatic evolution of breast carcinoma. A 78-year-old woman had been diagnosed with carcinoma of the left mammary gland 4 years earlier and underwent mastectomy, bilateral axillary dissection, radiotherapy, chemotherapy and hormone therapy. She presented to our dermatology department, complaining of an infiltrated lesion of the right upper eyelid, lasting for 1 year, with conjunctivitis, which was resistant to local treatment started. An initial diagnosis of cicatricial pemphigoid was assumed by her dermatologist. Clinical examination showed an infiltrated and indurated lesion of the right upper eyelid, responsible for blepharoptosis, incomplete eyelid occlusion and conjunctivitis, without synechia or altered visual acuity (figure 1A). The left eye was normal. No peripheral lymph nodes were palpable and clinical examination was otherwise unremarkable. She had only taken tamoxifen since remission of the initial tumour. Histopathologic examination of skin biopsies showed dermal tumour infiltration, which strongly expressed cytokeratin 7 and 20 and oestrogen receptor (figures 1B-C). Immunofluorescence was negative. Diagnosis of breast carcinoma metastasis was confirmed. Extensive investigations revealed a motheaten pattern of osteolysis in the vertex and two sclerotic lesions, compatible with right osseous parietal metastasis, without visceral or deep lymph node metastasis. Bone scintigraphy confirmed vertex bone metastasis and revealed two more lesions of the pelvis and left humerus. Levels of the tumour marker cancer antigen 15.3 were normal. Given the combination of eyelid metastasis and metastatic bone lesions, her oncologist replaced tamoxifen treatment with letrozole. Six months later, there was partial improvement of the right palpebral infiltration but with increased conjunctivitis. We report an eyelid lesion that was the first sign of systemic metastatic disease with multifocal bone lesions of a breast carcinoma quiescent for 4 years. Kanitakis [1] and
A
B
C
Figure 1. A) Blepharoptosis and conjunctivitis induced by an infiltrated lesion of the right eyelid. B) Cutaneous histology HES. Dermal tumoral infiltration. C) Immunohistochemistry analysis of cutaneous histology: cytokeratin 7 positive staining.
81
Tomasini [2] also reported similar cases of eyelid metastasis in a patient with a history of breast carcinoma. Extensive investigations revealed systemic metastatic disease. Metastases of the eyelids are particularly rare and represent less than 1% of all eyelid tumours [6, 7]. These lesions are most frequently localized in the choroid, orbit or ciliary body [3-5] and are mostly unilateral, but two cases with involvement of four eyelids have been reported [7]. Multiple primary cancers may be responsible for such metastasis, but breast cancer is the most common origin (35-48%) [6, 7, 9] and usually reaches subcutaneous tissue of the upper eyelid [10]. Usually, a single nodule of the eyelid is described. Flat pigmented lesions, diffuse oedema of the eyelids and epiphora have also been reported [7]. Rarely, blepharoptosis or ulcerated lesions can be seen [10]. Eyelid ptosis associated with infiltration and conjunctivitis is quite atypical. Among atypical manifestations, some of them may suggest a differential diagnosis, ophthalmological or dermatological, and skin biopsy is necessary to confirm the diagnosis of eyelid metastasis. Mansour et al. [8] examined 31 patients with metastatic disease to the eyelid, metastasis was suspected in only 32% of the cases. Most common misdiagnoses were chalazion, cyst, granuloma and xanthoma, but also malignant tumours like basal cell carcinoma, squamous cell carcinoma, melanoma, Merkel tumour and sebaceous carcinoma. Histopathological examination may indicate the architecture of primitive carcinoma, with tumoral cell proliferation and immunohistochemistry markers towards the primary cancer, but sometimes it can be difficult to interpret the variable clinicopathological appearance of metastatic breast carcinoma [2]. The time of onset of eyelid metastases varies, from 4 to 120 months after diagnosis of the primary carcinoma [6, 8-10]. Although rare, the lesions can be the first sign of systemic disease and reveal the underlying cancer in 7-45% of cases [6, 8-10]. Several treatment options have been proposed, depending on the secondary locations. Surgical resection may be used in cases of single lesions of the eyelid. Radiation therapy may be useful in cases of multiple or recurrent lesions. In cases of systemic disease, with multifocal lesions, systemic treatments should be considered, including hormonal therapy, or chemotherapy [10]. We report a case of blepharoptosis associated with conjunctivitis, reflecting metastatic breast carcinoma. Diagnosis of eyelid metastasis, although misleading, must be considered in any eyelid lesion in patients with a known history of cancer, to avoid diagnostic delay and improve the local and general prognosis of cancer. Disclosure. Financial support: none. Conflict of interest: none. Dermatology department, Nancy University Hospital, Hôpitaux de Brabois, rue du Morvan, 54500 Vandoeuvre-lès-Nancy, France
Marie LARQUEY Anne Claire BURSZTEJN Claire POREAUX Jean-Franc¸ois CUNY Jean-Luc SCHMUTZ
1. Kanitakis J, Faure M, Claudy A. Clinical picture : eyelid metastasis. The Lancet 2001; 358: 33.
82
2. Tomasini C, Soro E, Pippione E. Eyelid swelling : think of metastasis of histiocytoid breast carcinoma. Dermatology 2002; 205: 63-6. 3. Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit. A clinicopathologic study of 227 cases. Arch Ophthalmol 1974; 92: 276-86. 4. Bloch RS, Gartner S. The incidence of ocular metastatic carcinoma. Arch Ophthalmol 1971; 85: 673-5. 5. Hutchison DS, Smith TR. Ocular and orbital metastatic carcinoma. Ann Ophthalmol 1979; 11: 869-73. 6. Shields CL, Demirci H, Karatza E, et al. Clinical survey of 1643 melanocytic and non melanocytic conjunctival tumors. Ophthalmology 2004; 111: 1747-54. 7. Martorell-Calatayud A, Requena C, Diaz-Recuero JL, et al. Masklike metastasis: report of 2 cases of 4 eyelid metastases and review of the literature. Am J Dermatopath 2010; 32: 9-14. 8. Riley FC. Metastatic tumors of the eyelids. Am J Ophthalmol 1970; 69: 259-64. 9. Mansour AM, Hidayat AA. Metastatic eyelid disease. Ophthalmology 1987; 94: 667-70. 10. Bianciotto C, Demirci H, Shields CL, et al. Metastatic tumors of the eyelid: report of 20 cases and review of the literature. Arch Ophthalmol 2009; 127: 999-1005. doi:10.1684/ejd.2014.2455
Langerhans cell histiocytosis involving the skin and the thymus Langerhans cell histiocytosis (LCH) is a rare neoplastic proliferation of dendritic cells resembling Langerhans cells, which can accumulate in various organs. Thymic involvement (TI) is rare, probably underestimated, and its management and prognosis are not well established. We report a 5-month-old male infant who presented with asymptomatic skin lesions on the scalp and trunk (figure 1A). Histology and immunohistochemistry of one of the trunk lesions showed a dermal and epidermal infiltration with CD1a+/CD207(langerin)+ cells (figures 1B,D), confirming the diagnosis of LCH. The patient underwent checkup to rule out systemic disease. Clinical examination, blood analysis, whole body bone scintigraphy, abdominal ultrasound examination and chest X-rays showed no evidence of disseminated disease. Consequently, the patient was diagnosed with purely cutaneous LCH. No treatment was initiated; instead, the patient was regularly followed (every 3 months for 6 months, then yearly). Searching for the BRAFV600E mutation, reportedly present in half and two-thirds of LCH cases in adults and children respectively [1], could not be performed for technical reasons. Two months later, the patient underwent cardiac surgery during which the thymus was found to be hard and enlarged, motivating subtotal thymectomy. Histological examination of the thymus, including immunohistochemistry for CD1a and CD207/langerin, showed involvement by LCH (figure 1C). The BRAFV600E mutation was detected by molecular analysis. The infant was therefore diagnosed with cutaneous and thymic LCH. One year after surgery, the patient is well and shows no recurrence of LCH. The cutaneous lesions disappeared and neither hepatosplenomegaly nor adenopathy has developed. Chest X-ray and thymic ultrasound examinations were normal. The patient is being examined annually on an outpatient basis in hematology. EJD, vol. 25, n◦ 1, January-February 2015
Division of Dermatology, Laboratory of Genetic Skin Diseases, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan 3 Morishita Dermatology Clinic, Nagaoka, Japan 2
Ryota HAYASHI1,2 Hiroshi FUJIWARA1 Michiko MORISHITA3 Masaaki ITO1 Yutaka SHIMOMURA2
1. de Zwart-Storm EA, Hamm H, Stoevesandt J, et al. A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness. J Med Genet 2008; 45: 161-6. 2. Richard G, Rouan F, Willoughby CE, et al. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitisichthyosis-deafness syndrome. Am J Hum Genet 2002; 70: 1341-8. 3. Richard G, Brown N, Ishida-Yamamoto A, Krol A. Expanding the phenotypic spectrum of Cx26 disorders: Bart-Pumphrey syndrome is caused by a novel missense mutation in GJB2. J Invest Dermatol 2004; 123: 856-63. 4. Jan AY, Amin S, Ratajczak P, Richard G, Sybert VP. Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. J Invest Dermatol 2004; 122: 1108-13. 5. Sevior KB, Hatamochi A, Stewart IA, et al. Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness. Am J Med Genet 1998; 75: 179-85. 6. Smith FJ, Morley SM, McLean WH. A novel connexin 30 mutation in Clouston syndrome. J Invest Dermatol 2002; 118: 530-2. 7. Reid FM, Rovio A, Holt IJ, Jacobs HT. Molecular phenotype of a human lymphoblastoid cell-line homoplasmic for the np 7445 deafnessassociated mitochondrial mutation. Hum Mol Genet 1997; 6: 443-9. 8. Reid FM, Vernham GA, Jacobs HT. A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum Mut 1994; 3: 243-7. 9. Martin L, Toutain A, Guillen C, et al. Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome. Br J Dermatol 2000; 143: 87683. EJD, vol. 25, n◦ 1, January-February 2015
10. Caria H, Matos S, Oliveira-Soares R, et al. A7445G mtDNA mutation present in a Portuguese family exhibiting hereditary deafness and palmoplantar keratoderma. J Eur Acad Dermatol Venereol 2005; 19: 455-8. doi:10.1684/ejd.2014.2461
Blepharoconjunctivitis and an unusual location of metastatic breast carcinoma Eyelid metastases represent less than 1% of malignant eyelid lesions. We report a case of single right-eyelid infiltration, which revealed metastatic evolution of breast carcinoma. A 78-year-old woman had been diagnosed with carcinoma of the left mammary gland 4 years earlier and underwent mastectomy, bilateral axillary dissection, radiotherapy, chemotherapy and hormone therapy. She presented to our dermatology department, complaining of an infiltrated lesion of the right upper eyelid, lasting for 1 year, with conjunctivitis, which was resistant to local treatment started. An initial diagnosis of cicatricial pemphigoid was assumed by her dermatologist. Clinical examination showed an infiltrated and indurated lesion of the right upper eyelid, responsible for blepharoptosis, incomplete eyelid occlusion and conjunctivitis, without synechia or altered visual acuity (figure 1A). The left eye was normal. No peripheral lymph nodes were palpable and clinical examination was otherwise unremarkable. She had only taken tamoxifen since remission of the initial tumour. Histopathologic examination of skin biopsies showed dermal tumour infiltration, which strongly expressed cytokeratin 7 and 20 and oestrogen receptor (figures 1B-C). Immunofluorescence was negative. Diagnosis of breast carcinoma metastasis was confirmed. Extensive investigations revealed a motheaten pattern of osteolysis in the vertex and two sclerotic lesions, compatible with right osseous parietal metastasis, without visceral or deep lymph node metastasis. Bone scintigraphy confirmed vertex bone metastasis and revealed two more lesions of the pelvis and left humerus. Levels of the tumour marker cancer antigen 15.3 were normal. Given the combination of eyelid metastasis and metastatic bone lesions, her oncologist replaced tamoxifen treatment with letrozole. Six months later, there was partial improvement of the right palpebral infiltration but with increased conjunctivitis. We report an eyelid lesion that was the first sign of systemic metastatic disease with multifocal bone lesions of a breast carcinoma quiescent for 4 years. Kanitakis [1] and
A
B
C
Figure 1. A) Blepharoptosis and conjunctivitis induced by an infiltrated lesion of the right eyelid. B) Cutaneous histology HES. Dermal tumoral infiltration. C) Immunohistochemistry analysis of cutaneous histology: cytokeratin 7 positive staining.
81
Tomasini [2] also reported similar cases of eyelid metastasis in a patient with a history of breast carcinoma. Extensive investigations revealed systemic metastatic disease. Metastases of the eyelids are particularly rare and represent less than 1% of all eyelid tumours [6, 7]. These lesions are most frequently localized in the choroid, orbit or ciliary body [3-5] and are mostly unilateral, but two cases with involvement of four eyelids have been reported [7]. Multiple primary cancers may be responsible for such metastasis, but breast cancer is the most common origin (35-48%) [6, 7, 9] and usually reaches subcutaneous tissue of the upper eyelid [10]. Usually, a single nodule of the eyelid is described. Flat pigmented lesions, diffuse oedema of the eyelids and epiphora have also been reported [7]. Rarely, blepharoptosis or ulcerated lesions can be seen [10]. Eyelid ptosis associated with infiltration and conjunctivitis is quite atypical. Among atypical manifestations, some of them may suggest a differential diagnosis, ophthalmological or dermatological, and skin biopsy is necessary to confirm the diagnosis of eyelid metastasis. Mansour et al. [8] examined 31 patients with metastatic disease to the eyelid, metastasis was suspected in only 32% of the cases. Most common misdiagnoses were chalazion, cyst, granuloma and xanthoma, but also malignant tumours like basal cell carcinoma, squamous cell carcinoma, melanoma, Merkel tumour and sebaceous carcinoma. Histopathological examination may indicate the architecture of primitive carcinoma, with tumoral cell proliferation and immunohistochemistry markers towards the primary cancer, but sometimes it can be difficult to interpret the variable clinicopathological appearance of metastatic breast carcinoma [2]. The time of onset of eyelid metastases varies, from 4 to 120 months after diagnosis of the primary carcinoma [6, 8-10]. Although rare, the lesions can be the first sign of systemic disease and reveal the underlying cancer in 7-45% of cases [6, 8-10]. Several treatment options have been proposed, depending on the secondary locations. Surgical resection may be used in cases of single lesions of the eyelid. Radiation therapy may be useful in cases of multiple or recurrent lesions. In cases of systemic disease, with multifocal lesions, systemic treatments should be considered, including hormonal therapy, or chemotherapy [10]. We report a case of blepharoptosis associated with conjunctivitis, reflecting metastatic breast carcinoma. Diagnosis of eyelid metastasis, although misleading, must be considered in any eyelid lesion in patients with a known history of cancer, to avoid diagnostic delay and improve the local and general prognosis of cancer. Disclosure. Financial support: none. Conflict of interest: none. Dermatology department, Nancy University Hospital, Hôpitaux de Brabois, rue du Morvan, 54500 Vandoeuvre-lès-Nancy, France
Marie LARQUEY Anne Claire BURSZTEJN Claire POREAUX Jean-Franc¸ois CUNY Jean-Luc SCHMUTZ
1. Kanitakis J, Faure M, Claudy A. Clinical picture : eyelid metastasis. The Lancet 2001; 358: 33.
82
2. Tomasini C, Soro E, Pippione E. Eyelid swelling : think of metastasis of histiocytoid breast carcinoma. Dermatology 2002; 205: 63-6. 3. Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit. A clinicopathologic study of 227 cases. Arch Ophthalmol 1974; 92: 276-86. 4. Bloch RS, Gartner S. The incidence of ocular metastatic carcinoma. Arch Ophthalmol 1971; 85: 673-5. 5. Hutchison DS, Smith TR. Ocular and orbital metastatic carcinoma. Ann Ophthalmol 1979; 11: 869-73. 6. Shields CL, Demirci H, Karatza E, et al. Clinical survey of 1643 melanocytic and non melanocytic conjunctival tumors. Ophthalmology 2004; 111: 1747-54. 7. Martorell-Calatayud A, Requena C, Diaz-Recuero JL, et al. Masklike metastasis: report of 2 cases of 4 eyelid metastases and review of the literature. Am J Dermatopath 2010; 32: 9-14. 8. Riley FC. Metastatic tumors of the eyelids. Am J Ophthalmol 1970; 69: 259-64. 9. Mansour AM, Hidayat AA. Metastatic eyelid disease. Ophthalmology 1987; 94: 667-70. 10. Bianciotto C, Demirci H, Shields CL, et al. Metastatic tumors of the eyelid: report of 20 cases and review of the literature. Arch Ophthalmol 2009; 127: 999-1005. doi:10.1684/ejd.2014.2455
Langerhans cell histiocytosis involving the skin and the thymus Langerhans cell histiocytosis (LCH) is a rare neoplastic proliferation of dendritic cells resembling Langerhans cells, which can accumulate in various organs. Thymic involvement (TI) is rare, probably underestimated, and its management and prognosis are not well established. We report a 5-month-old male infant who presented with asymptomatic skin lesions on the scalp and trunk (figure 1A). Histology and immunohistochemistry of one of the trunk lesions showed a dermal and epidermal infiltration with CD1a+/CD207(langerin)+ cells (figures 1B,D), confirming the diagnosis of LCH. The patient underwent checkup to rule out systemic disease. Clinical examination, blood analysis, whole body bone scintigraphy, abdominal ultrasound examination and chest X-rays showed no evidence of disseminated disease. Consequently, the patient was diagnosed with purely cutaneous LCH. No treatment was initiated; instead, the patient was regularly followed (every 3 months for 6 months, then yearly). Searching for the BRAFV600E mutation, reportedly present in half and two-thirds of LCH cases in adults and children respectively [1], could not be performed for technical reasons. Two months later, the patient underwent cardiac surgery during which the thymus was found to be hard and enlarged, motivating subtotal thymectomy. Histological examination of the thymus, including immunohistochemistry for CD1a and CD207/langerin, showed involvement by LCH (figure 1C). The BRAFV600E mutation was detected by molecular analysis. The infant was therefore diagnosed with cutaneous and thymic LCH. One year after surgery, the patient is well and shows no recurrence of LCH. The cutaneous lesions disappeared and neither hepatosplenomegaly nor adenopathy has developed. Chest X-ray and thymic ultrasound examinations were normal. The patient is being examined annually on an outpatient basis in hematology. EJD, vol. 25, n◦ 1, January-February 2015
