- Email: [email protected]
Loss of heterozygosity in a case of glomuvenous malformations
1656
1592
HaileyeHailey disease: A case report Gagan Goyal, MBBS, Sri Aurobindo Medical College and PG Institute, Indore, India; Hitesh Lokwani, MBBS, Sri Aurobindo Medical College and PG Institute, Indore, India; Kailsah Bhatia, MD, Sri Aurobindo Medical College and PG Institute, Indore, India; Rajesh Kataria, MD, Sri Aurobindo Medical College and PG Insitute, Indore, India
Maffucci syndrome: A case report Celia Sanchis Sanchez, Hospital Universitario Doctor Peset, Valencia, Spain; Sofıa De Asıs Cuestas, Hospital Universitario Doctor Peset, Valencia, Spain; Sergio Santos Alarc on, Hospital Universitario Doctor Peset, Valencia, Spain; Felipe Cesar Benavente Villegas, Hospital Universitario Doctor Peset, Valencia, Spain; Almudena Mateu Puchades, Hospital Universitario Doctor Peset, Valencia, Spain; Amparo Marquina Vila, Hospital Universitario Doctor Peset, Valencia, Spain; Francisco Garcıa Herreros, Hospital Universitario Doctor Peset, Valencia, Spain Introduction: Maffucci syndrome is a rare nonhereditary disorder characterized by the coexistence of multiple enchondromas, vascular lesions and skeletal anomalies. Since its first description in 1881, approximately 200 cases have been reported worldwide with no sex or racial preference. Case report: We report the case of a 28-year-old male with a secondary panhypopituitarism after excision of a cerebral enchondroma who presented with asymptomatic lesions on the hands since adolescence. The physical examination revealed two types of subcutaneous lesions: mobile bluish soft nodules with a vascular appearance; and hard nodular lesions that suggested a bony origin. He also had a significant scoliosis and a dysmetria of the limbs, with shortening and varus deformity of the right extremities. Radiologic studies revealed that the lesions with bony appearance were enchondromas; and histologic examination of a nodule with vascular appearance showed a spindle cell hemangioma.
Introduction: HaileyeHailey disease or familial benign chronic pemphigus is characterized by cutaneous involvement in the form of vesiculopustules, painful erosions, and scaly erythematous plaques usually appear on the site of friction such as axilla, neck, groins and perineum. It is a rare intra-epidermal blistering disease inherited in autosomal dominant fashion with prevalence of around 1 in 50,000. Positive family history is observed in about 75% of cases. Usually the disease is presented in 3rd and 4th decade of life. Here we present a case of HaileyeHailey disease in which presentation of disease was occurred at 5th decade. Case report: A 55-year-old male presented with symptoms of recurrent vesicles and painful scaly erosions in the intertriginous areas such as axilla and groins. The lesions were pruritic and associated with stinging sensation. Patient had a 2-year history of recurrent periods of exacerbations throughout the summer months. The patient had been treated in the past with topical and systemic antifungal as well as antibiotics but was refractory to all kinds of treatment. History of similar complaints in the family in second degree relative was present. KOH smear for fungus was negative, Histopathology of the lesion revealed intraepidermal acantholysis; immunofluorescence was negative which are consistent with HaileyeHailey disease. All the routine lab investigations were within normal limits. Topical steroids with antimicrobial cleanser were given for a month. Patient responds well to the treatment after one month. Patient was advised to avoid friction and sweating. Conclusion: In our patient the age of presentation of disease was late and therefore it is a rare case. Commercial support: None identified.
Discussion: Maffucci syndrome is due to a congenital mesodermal dysplasia which etiology is still unknown, although a recent study has identified mutations in the isocitrate dehydrogenase (IDH) proteins 1 and 2 in both cartilaginous and vascular tumors. Clinically, affected persons usually appear without anomalies at birth, and the disease manifests generally in early childhood with progressive development of nodular lesions, mainly on the distal extremities. Enchondromas are benign cartilaginous tumors that may develop complications, such as deformities, spontaneous fractures, and malignant degeneration into chondrosarcomas, which occurs in approximately 30% to 40% of the cases. Even though chondrosarcomas are by far the most common neoplasm encountered, Maffucci syndrome is associated with many other malignancies (astrocytoma, pancreatic adenocarcinoma.), but despite the range of neoplasms is broad, vascular malignancy has only been rarely reported. There is no curative treatment, and surgery is only indicated in case of complications. Thus, management of this syndrome is focused at the relief of symptoms and early detection of malignancies, so that regular examinations are necessary to monitor for any change that may suggest a malignant transformation. Commercial support: None identified.
1101 Loss of heterozygosity in a case of glomuvenous malformations Chika Ohata, MD, PhD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Mitsuhiro Matsuda, MD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Takahiro Hamada, MD, PhD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Kwesi Teye, PhD, Kurume University Institute of Cutaneous Cell Biology, Fukuoka, Japan; Sanae Numata, PhD, Kurume University Institute of Cutaneous Cell Biology, Fukuoka, Japan; Takako Shintani, MD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Ikko Muto, MD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Minao Furumura, MD, PhD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Takekuni Nakama, MD, PhD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan Glomuvenous malformations (GVM), also known as glomangiomas, have features of both glomus-cell proliferations and vascular malformations. The causative gene is the glomulin gene (GLMN), which is located on the short arm of chromosome 1 (1p22.1). GVM is an autosomal dominant disease with incomplete penetrance and variable expressivity. We report a case of GVM with loss of heterozygosity (LOH). A 29-year-old Japanese man presented with several painful bluish skin nodules that had appeared 12 years earlier. The patient had epilepsy but was otherwise healthy. Although his mother also had epilepsy, no family members had GVM. Physical examination revealed aggregations of bluish nodules, each of which was approximately 5 mm in diameter, on the left forearm, left lower back and right thigh. A biopsy of a back lesion revealed GVM. Subsequently, we performed sequence analysis of the GLMN gene using DNA samples taken from both peripheral blood and skin lesions after obtaining informed consent, with approval of the ethics committee of Kurume University. Heterozygous and homozygous mutations (c.1150_1151delAG) were identified in exon 13 from peripheral blood DNA and skin lesion DNA, respectively. LOH in the skin lesion DNA was identified by microsatellite marker studies using D1S435 and D1S2868, both of which are located around the GLMN locus. A GLMN mutation has been found in 162 families to date. There are 40 different mutations, and c.157_161del is the most frequent mutation found in 44.4% patients. Only two families had c.1150_1151delAG. GVM is confined to limited skin areas. The expressivity of the phenotype is variable for the same mutation. Not all family members harboring a mutation are affected. Considering these facts, a second-hit somatic mutation may be necessary in addition to a germline mutation. In 2002, one case with the 980delCAGAA somatic mutation in a lesion in a patient harboring an inherited large genomic deletion in the GLMN gene, was reported. However, in 2011, no second-hit somatic mutation was identified in an Italian family. Recently, 16 somatic second-hit mutations were identified in 28 GVMs. In this study, 6 samples with an inherited mutation of c.395-1G [ A, c.107dup, c.157_161del, c.395-1G [ C, or c.743dup demonstrated LOH. The present case showed another LOH in c.1150_1151delAG. A second-hit somatic mutation has not been identified in some cases of GVM; however, the present case added some legitimacy to this hypothesis. Commercial support: None identified.
MAY 2015
1054 Multiple familial trichoepithelioma: Report of a Spanish family associated with a mutation in the CYLD gene Laura Cubells Sanchez, Department of Dermatology and Venereology of Consorcio Hospital Universitario de Valencia, Valencia, Spain; Nikoletta Nagy, Department of Medical Genetics, University of Szeged, Szeged, Hungary; Ana Mercedes Victoria Martınez, Department of Dermatology and Venereology of Consorcio Hospital Universitario de Valencia, Valencia, Spain; Marıa Teresa Rico Fernandez, Department of Dermatology and Venereology of Consorcio Hospital Universitario de Valencia, Valencia, Spain; Marta Szell, Department of Medical Genetics, University of Szeged, Hungary; Katalin Farkas, Dermatologic Research Group of the Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary; Raquel Rodrıguez L opez, Genetics Laboratory of Consorcio Hospital General Universitario de Valencia, Valencia, Spain; Jose Marıa Ortız Salvador, Department of Dermatology and Venereology of Consorcio Hospital Universitario de Valencia, Valencia, Spain; Juan Jose Vilata Corell, Department of Dermatology and Venereology of Consorcio Hospital Universitario de Valencia, Valencia, Spain Introduction: Multiple familial trichoepithelioma type 1 (MFT; MIM 601606), a rare, monogenic skin disease with autosomal dominant inheritance, is characterized by the development of multiple skin-colored papules on the central area of the face. It is associated with various CYLD gene mutations that are also responsible for familial cylindromatosis (FC) and BrookeeSpiegler syndrome (BSS). Case report: Recently we have identified a Spanish MFT pedigree with two affected family members (father and daughter). Direct sequencing of the CYLD gene revealed a nonsense mutation (c.2272C/T, p.R758X) in exon 17. This mutation leads to the formation of a premature termination codon and produces truncated dysfunctional CYLD protein. The patients carried the mutation in heterozygous form, while the clinically-unaffected family members and the unrelated controls carried only the wild type sequence. A reviewing of previous reports has revealed that thec.2272C/T, p.R758X nonsense mutation has already been detected in patients with all three clinical variants (BSS, familial cylindromatosis and multiple familial trichoepithelioma type 1) of the CYLD-mutation spectrum, associated with high phenotypic diversity. Conclusion: The c.2272C/T, p.R758X nonsense mutation of the CYLD gene can lead to the manifestation of any of the clinical variants of the spectrum caused by CYLDmutation associated with high phenotypic diversity: Multiple familial trichoepithelioma, familial cylindromatosis and BrookeeSpiegler syndrome. This recurrent nonsense mutation has been reported worldwide suggesting a mutational hotspot on the gene. Commercial support: None identified.
J AM ACAD DERMATOL
AB107
1592
HaileyeHailey disease: A case report Gagan Goyal, MBBS, Sri Aurobindo Medical College and PG Institute, Indore, India; Hitesh Lokwani, MBBS, Sri Aurobindo Medical College and PG Institute, Indore, India; Kailsah Bhatia, MD, Sri Aurobindo Medical College and PG Institute, Indore, India; Rajesh Kataria, MD, Sri Aurobindo Medical College and PG Insitute, Indore, India
Maffucci syndrome: A case report Celia Sanchis Sanchez, Hospital Universitario Doctor Peset, Valencia, Spain; Sofıa De Asıs Cuestas, Hospital Universitario Doctor Peset, Valencia, Spain; Sergio Santos Alarc on, Hospital Universitario Doctor Peset, Valencia, Spain; Felipe Cesar Benavente Villegas, Hospital Universitario Doctor Peset, Valencia, Spain; Almudena Mateu Puchades, Hospital Universitario Doctor Peset, Valencia, Spain; Amparo Marquina Vila, Hospital Universitario Doctor Peset, Valencia, Spain; Francisco Garcıa Herreros, Hospital Universitario Doctor Peset, Valencia, Spain Introduction: Maffucci syndrome is a rare nonhereditary disorder characterized by the coexistence of multiple enchondromas, vascular lesions and skeletal anomalies. Since its first description in 1881, approximately 200 cases have been reported worldwide with no sex or racial preference. Case report: We report the case of a 28-year-old male with a secondary panhypopituitarism after excision of a cerebral enchondroma who presented with asymptomatic lesions on the hands since adolescence. The physical examination revealed two types of subcutaneous lesions: mobile bluish soft nodules with a vascular appearance; and hard nodular lesions that suggested a bony origin. He also had a significant scoliosis and a dysmetria of the limbs, with shortening and varus deformity of the right extremities. Radiologic studies revealed that the lesions with bony appearance were enchondromas; and histologic examination of a nodule with vascular appearance showed a spindle cell hemangioma.
Introduction: HaileyeHailey disease or familial benign chronic pemphigus is characterized by cutaneous involvement in the form of vesiculopustules, painful erosions, and scaly erythematous plaques usually appear on the site of friction such as axilla, neck, groins and perineum. It is a rare intra-epidermal blistering disease inherited in autosomal dominant fashion with prevalence of around 1 in 50,000. Positive family history is observed in about 75% of cases. Usually the disease is presented in 3rd and 4th decade of life. Here we present a case of HaileyeHailey disease in which presentation of disease was occurred at 5th decade. Case report: A 55-year-old male presented with symptoms of recurrent vesicles and painful scaly erosions in the intertriginous areas such as axilla and groins. The lesions were pruritic and associated with stinging sensation. Patient had a 2-year history of recurrent periods of exacerbations throughout the summer months. The patient had been treated in the past with topical and systemic antifungal as well as antibiotics but was refractory to all kinds of treatment. History of similar complaints in the family in second degree relative was present. KOH smear for fungus was negative, Histopathology of the lesion revealed intraepidermal acantholysis; immunofluorescence was negative which are consistent with HaileyeHailey disease. All the routine lab investigations were within normal limits. Topical steroids with antimicrobial cleanser were given for a month. Patient responds well to the treatment after one month. Patient was advised to avoid friction and sweating. Conclusion: In our patient the age of presentation of disease was late and therefore it is a rare case. Commercial support: None identified.
Discussion: Maffucci syndrome is due to a congenital mesodermal dysplasia which etiology is still unknown, although a recent study has identified mutations in the isocitrate dehydrogenase (IDH) proteins 1 and 2 in both cartilaginous and vascular tumors. Clinically, affected persons usually appear without anomalies at birth, and the disease manifests generally in early childhood with progressive development of nodular lesions, mainly on the distal extremities. Enchondromas are benign cartilaginous tumors that may develop complications, such as deformities, spontaneous fractures, and malignant degeneration into chondrosarcomas, which occurs in approximately 30% to 40% of the cases. Even though chondrosarcomas are by far the most common neoplasm encountered, Maffucci syndrome is associated with many other malignancies (astrocytoma, pancreatic adenocarcinoma.), but despite the range of neoplasms is broad, vascular malignancy has only been rarely reported. There is no curative treatment, and surgery is only indicated in case of complications. Thus, management of this syndrome is focused at the relief of symptoms and early detection of malignancies, so that regular examinations are necessary to monitor for any change that may suggest a malignant transformation. Commercial support: None identified.
1101 Loss of heterozygosity in a case of glomuvenous malformations Chika Ohata, MD, PhD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Mitsuhiro Matsuda, MD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Takahiro Hamada, MD, PhD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Kwesi Teye, PhD, Kurume University Institute of Cutaneous Cell Biology, Fukuoka, Japan; Sanae Numata, PhD, Kurume University Institute of Cutaneous Cell Biology, Fukuoka, Japan; Takako Shintani, MD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Ikko Muto, MD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Minao Furumura, MD, PhD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan; Takekuni Nakama, MD, PhD, Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan Glomuvenous malformations (GVM), also known as glomangiomas, have features of both glomus-cell proliferations and vascular malformations. The causative gene is the glomulin gene (GLMN), which is located on the short arm of chromosome 1 (1p22.1). GVM is an autosomal dominant disease with incomplete penetrance and variable expressivity. We report a case of GVM with loss of heterozygosity (LOH). A 29-year-old Japanese man presented with several painful bluish skin nodules that had appeared 12 years earlier. The patient had epilepsy but was otherwise healthy. Although his mother also had epilepsy, no family members had GVM. Physical examination revealed aggregations of bluish nodules, each of which was approximately 5 mm in diameter, on the left forearm, left lower back and right thigh. A biopsy of a back lesion revealed GVM. Subsequently, we performed sequence analysis of the GLMN gene using DNA samples taken from both peripheral blood and skin lesions after obtaining informed consent, with approval of the ethics committee of Kurume University. Heterozygous and homozygous mutations (c.1150_1151delAG) were identified in exon 13 from peripheral blood DNA and skin lesion DNA, respectively. LOH in the skin lesion DNA was identified by microsatellite marker studies using D1S435 and D1S2868, both of which are located around the GLMN locus. A GLMN mutation has been found in 162 families to date. There are 40 different mutations, and c.157_161del is the most frequent mutation found in 44.4% patients. Only two families had c.1150_1151delAG. GVM is confined to limited skin areas. The expressivity of the phenotype is variable for the same mutation. Not all family members harboring a mutation are affected. Considering these facts, a second-hit somatic mutation may be necessary in addition to a germline mutation. In 2002, one case with the 980delCAGAA somatic mutation in a lesion in a patient harboring an inherited large genomic deletion in the GLMN gene, was reported. However, in 2011, no second-hit somatic mutation was identified in an Italian family. Recently, 16 somatic second-hit mutations were identified in 28 GVMs. In this study, 6 samples with an inherited mutation of c.395-1G [ A, c.107dup, c.157_161del, c.395-1G [ C, or c.743dup demonstrated LOH. The present case showed another LOH in c.1150_1151delAG. A second-hit somatic mutation has not been identified in some cases of GVM; however, the present case added some legitimacy to this hypothesis. Commercial support: None identified.
MAY 2015
1054 Multiple familial trichoepithelioma: Report of a Spanish family associated with a mutation in the CYLD gene Laura Cubells Sanchez, Department of Dermatology and Venereology of Consorcio Hospital Universitario de Valencia, Valencia, Spain; Nikoletta Nagy, Department of Medical Genetics, University of Szeged, Szeged, Hungary; Ana Mercedes Victoria Martınez, Department of Dermatology and Venereology of Consorcio Hospital Universitario de Valencia, Valencia, Spain; Marıa Teresa Rico Fernandez, Department of Dermatology and Venereology of Consorcio Hospital Universitario de Valencia, Valencia, Spain; Marta Szell, Department of Medical Genetics, University of Szeged, Hungary; Katalin Farkas, Dermatologic Research Group of the Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary; Raquel Rodrıguez L opez, Genetics Laboratory of Consorcio Hospital General Universitario de Valencia, Valencia, Spain; Jose Marıa Ortız Salvador, Department of Dermatology and Venereology of Consorcio Hospital Universitario de Valencia, Valencia, Spain; Juan Jose Vilata Corell, Department of Dermatology and Venereology of Consorcio Hospital Universitario de Valencia, Valencia, Spain Introduction: Multiple familial trichoepithelioma type 1 (MFT; MIM 601606), a rare, monogenic skin disease with autosomal dominant inheritance, is characterized by the development of multiple skin-colored papules on the central area of the face. It is associated with various CYLD gene mutations that are also responsible for familial cylindromatosis (FC) and BrookeeSpiegler syndrome (BSS). Case report: Recently we have identified a Spanish MFT pedigree with two affected family members (father and daughter). Direct sequencing of the CYLD gene revealed a nonsense mutation (c.2272C/T, p.R758X) in exon 17. This mutation leads to the formation of a premature termination codon and produces truncated dysfunctional CYLD protein. The patients carried the mutation in heterozygous form, while the clinically-unaffected family members and the unrelated controls carried only the wild type sequence. A reviewing of previous reports has revealed that thec.2272C/T, p.R758X nonsense mutation has already been detected in patients with all three clinical variants (BSS, familial cylindromatosis and multiple familial trichoepithelioma type 1) of the CYLD-mutation spectrum, associated with high phenotypic diversity. Conclusion: The c.2272C/T, p.R758X nonsense mutation of the CYLD gene can lead to the manifestation of any of the clinical variants of the spectrum caused by CYLDmutation associated with high phenotypic diversity: Multiple familial trichoepithelioma, familial cylindromatosis and BrookeeSpiegler syndrome. This recurrent nonsense mutation has been reported worldwide suggesting a mutational hotspot on the gene. Commercial support: None identified.
J AM ACAD DERMATOL
AB107