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Granulomatous skin involvement in a patient with an unusual NOD2 mutation
966
1354
Epidermodysplasia verruciformis: A pediatric case report Irene Latour, MD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Marıa Pestana, MD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Estela Garcıa, MD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Cristina Vazquez, MD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Rosa Rodriguez, MD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Francisco Guimera, MD, PhD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Rosalba Sanchez, MD, PhD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain Introduction: Epidermodysplasia verruciformis (EV) is a rare cutaneous autosomal recessive genetic disorder of the immune system, caused by mutations in genes EVER1 or EVER2, both found in chromosome 17q25. People affected show an abnormal susceptibility to a specific group of human papillomavirus (HPV), most of them infected by the oncogenic HPV5 and HPV8. Patients with EV usually develop disseminated flat, wart-like lesions in childhood. Cutaneous carcinomas in situ and invasive squamous cell carcinomas develop in about half of patients during the third or fourth decade of life. Case report: An 11-year-old boy monitored in pediatrics due to the suspicion of imperfect osteogenesis (IO) and obesity. The patient was referred to dermatology department because he had multiple papules (over 100) with warty surface, of 0.30.4 cm diameter, with skin color; located on his face (forehead, supralabial, and cheeks), hands and flexures of both wrists. Skin biopsy of one of the lesions located in his face, revealed hyperkeratosis without acanthotic epidermis. Vacuolar cells were presented in the upper stratum malpighii and granular layer. The study by HPV PCR of one of the lesions was positive for HPV5. With these results, the diagnosis of EV was performed. The main treatment is a regular monitoring for an early diagnosis of possible skin tumors, insisting on a very strict sunscreen. Our patient started treatment with topical retinoid.
Fatal dilated cardiomyopathy in a patient with recessive dystrophic epidermolysis bullosa Alexa R. Shipman, MBBCh, Birmingham Children’s Hospital, Birmingham, United Kingdom; Celia Moss, MBBCh, Birmingham Children’s Hospital, Birmingham, United Kingdom; Ashish Chickermane, MBBCh, Birmingham Children’s Hospital, Birmingham, United States; Fiona Browne, MBBCh, Birmingham Children’s Hospital, Birmingham, United Kingdom We present a 14-year-old boy with recessive dystrophic epidermolysis bullosa (RDEB) complicated by fatal cardiomyopathy. Epidermolysis bullosa is a severe blistering genodermatosis. RDEB-generalized severe subtype is characterized by extensive skin blistering with mucosal involvement, scarring, poor dentition and malnutrition. Cardiomyopathy is a rare but recognized complication. Our patient was born to unrelated Indian parents. Extensive skin loss and fragility was noted at birth, along with atrophic scarring and mucosal involvement. He was referred to the national epidermolysis bullosa service for investigation. Skin biopsy showed dermoepidermal junction split, and indirect immunofluorescence showed absent collagen 7. Mutation analysis confirmed a homozygous, nonsense mutation Q251X in exon 6 of the COL7A1 gene, confirming the diagnosis of RDEB. Both parents were heterozygous carriers. Throughout his life he had severe, widespread skin damage. He was iron, selenium and zinc deficient from infancy, despite supplementation and regular transfusions. Esophagogastric erosions resulted in dysphagia, scarring and stricturing necessitating repeated esophageal dilatations and eventual gastrostomy feeding. Within 6 months of gastrostomy insertion he presented in acute respiratory distress. Cardiomegaly and pulmonary edema were evident on chest radiograph. Cardiac echocardiogram showed a dilated left ventricle (LV) with impaired systolic function at 12% (previous ECHOs normal). Viral cardiomyopathy screens were negative. He failed to respond to medical management with angiotensin converting enzyme inhibitors, inotropes and diuretics and passed away within a month of presentation, at the age of 14. Dilated cardiomyopathy is a documented risk in RDEB, with a 4.5% cumulative risk by age of 20 years. This increases to 18.86% by the age of 35 in patients that have concomitant renal failure. In at least 30% of patients the outcome is fatal. The etiology of cardiomyopathy in EB is uncertain. Hypotheses include micronutrient deficiency (carnitine, selenium), drugs, amyloidosis or chronic iron-overload. Our patient was both carnitine and selenium deficient and had become transfusion-dependent. We were unable to establish a precise cause for his cardiomyopathy but present this case to emphasize the risk of cardiomyopathy in EB patients and the need for regular routine ECHOs.
Conclusion: We present a case of a very uncommon genodermatosis which is the EV. In the literature review we found no association between IO and EV, however, it is known that mutation of the IO is in chromosome 17q21.3-q22 and the EV’s mutation is in 17q25. Genetic studies are needed in this patient but the location at the same locus in both entities could explain its coexistence. Commercial support: None identified.
Commercial support: None identified.
876 Familiar pachyonychia congenita due to p.Met88Arg mutation in the KRT17 gene Ana M. Victoria Martınez, MD, Consorci Hospital General Universitari Valencia, Valencia, Spain; Laura Cubells Sanchez, MD, Consorci Hospital General Universitari Valencia, Valencia, Spain; M. Teresa Rico Fernandez, MD, Consorci Hospital General Universitari Valencia, Valencia, Spain; Lorena Martınez Leborans, MD, Consorci Hospital General Universitari Valencia, Valencia, Spain; Raquel Rodrıguez L opez, MD, Consorci Hospital General Universitari Valencia, Valencia, Spain; Juan J. Vilata Corell, PhD, Consorci Hospital General Universitari Valencia, Valencia, Spain; Vicente Oliver Martınez, PhD, Consorci Hospital General Universitari Valencia, Valencia, Spain Pachyonychia congenita (PC) is a group of autosomal dominant, very rare keratinizing disorders, caused by a mutation in one of 5 keratin genes KRT6A, KRT6B, KRT6C, KRT16, and KRT17. We present a case of two women of the same family with diagnosis of PC. The first patient is a 32-year-old Spanish Caucasian woman who had a history of subcutaneous yellow nodules with a widespread distribution, especially in trunk and arms, since she was 15 years old. She also had plantar hyperkeratosis since childhood and congenital thickened toenails and fingernails. Her aunt, a woman of 56 years, had similar nail dystrophy, plantar hyperkeratosis and similar history of developing multiple cyst. Histologic examination of cysts showed that were steatocystomas. Patients knew the family nature of this alteration, affecting several members of their family over five generations, with a variable severity of disease manifestations. The pedigree of the family was studied and showed an autosomal dominant mode of inheritance. Genetic analysis of the proband and her aunt identified a heterozygous c.263T [ G (p.Met88Arg) mutation in the KRT17 gene, an infrequent mutation reported in PC-17, that, from our knowledge, has just been previously described in one family. The most common clinical findings in PC are painful, palmoplantar keratoderma and nail dystrophy. Other diagnostic findings associated are follicular hyperkeratosis, leukokeratosis, cysts, hoarseness, hyperhidrosis and natal teeth. During the first year of life, dystrophy of the fingernails and toenails occurs in most of the affected infants, providing an initial clue. By 5 years of age, plantar keratoderma is seen in most children. Traditionally, two sub-types of PC have been described: PC-1 (JadassohneLewandowsky type), caused by KRT6a or KRT16 mutations, associated with oral leucokeratosis and palmoplantar keratoderma, and PC-2 (JacksoneLawler type) resulting from KRT6b or KRT17 mutations, with neonatal teeth, pili torti and multiple cysts. However, recent case reports and case series have reported overlapping clinical features of PC-1 and PC-2 and the nomenclature has recently been revised based on the molecular genetic data; for example, this family with mutations in KRT17 should be named PC-K17. In conclusion, individuals presenting symptoms of PC should undergo genetic analysis for mutations in the five known PC genes. Correct molecular diagnosis is important to aid appropriate genetic counselling and patient care. Commercial support: None identified.
AB106
J AM ACAD DERMATOL
1408 Granulomatous skin involvement in a patient with an unusual NOD2 mutation Ifedayo O. Kuye, Harvard Medical School, Boston, MA, United States; Morayo Adisa, MD, Massachusetts General Hospital, Boston, MA, United States; Rosalynn M. Nazarian, MD, Massachusetts General Hospital, Boston, MA, United States; Sheila L. Arvikar, MD, Massachusetts General Hospital, Boston, MA, United States; Gideon P. Smith, MD, PhD, Massachusetts General Hospital, Boston, MA, United States A 54-year-old male on ustekinumab for a NOD2-associated inflammatory disorder with uveitis (with an unusual heterozygous c.1799A [ C(E600A) mutation), was seen for bilateral lower extremity swelling and pain. The patient reported a year-long history of pain in his legs, without overlying skin changes. The pain worsened five months ago and was accompanied by overlying skin erythema. He was initially treated for cellulitis with amoxicillin without improvement. A skin biopsy subsequently showed focal septal panniculitis consistent with erythema nodosum. He responded somewhat to prednisone taper, but had worsening below 10 mg daily. He also failed SSKI and NSAIDs. He had worsening pain necessitating use of a wheelchair and presented to us for a second opinion. On physical exam, the patient had lower leg edema with decreased hair growth on affected areas. There were no nodules or discrete patches of erythema, but there was severe tenderness to mild touch. Given his clinical presentation, we initially felt that the erythema nodosum may have resolved and that he was now presenting with pain secondary to lipodermatosclerosis. The patient was treated with colchicine for the possibility of residual inflammation, with excellent clinical response. However, the patient developed transaminitis, and colchicine dose was stopped. He had no response to either hydroxychloroquine or dapsone. Given his pain out of proportion to the physical findings a rebiopsy of the leg was then performed showing septal fibrosis with noncaseating microgranulomas, lipophages, and focal lipo-membranous changes in the subcutaneous fat. The symptoms thus seemed more consistent with granulomas secondary to his Blau-spectrum disease rather than erythema nodosum or lipodermatosclerosis. The patient is currently being managed with intralesional kenalog with good response. Given that this NOD2 mutation was previously described in the setting of uveitis without skin involvement, this report not only presents a case of an unusual genetic form of a rare condition, but it also demonstrates skin involvement in a subtype where cutaneous involvement had not been reported. In addition, the type and presentation of the skin involvement is different from that normally found in classic Blau Syndrome, and was misdiagnosed as erythema nodosum. Finally, we report response to colchicine, although ultimately not tolerated by this patient. Commercial support: None identified.
MAY 2015
1354
Epidermodysplasia verruciformis: A pediatric case report Irene Latour, MD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Marıa Pestana, MD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Estela Garcıa, MD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Cristina Vazquez, MD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Rosa Rodriguez, MD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Francisco Guimera, MD, PhD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain; Rosalba Sanchez, MD, PhD, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain Introduction: Epidermodysplasia verruciformis (EV) is a rare cutaneous autosomal recessive genetic disorder of the immune system, caused by mutations in genes EVER1 or EVER2, both found in chromosome 17q25. People affected show an abnormal susceptibility to a specific group of human papillomavirus (HPV), most of them infected by the oncogenic HPV5 and HPV8. Patients with EV usually develop disseminated flat, wart-like lesions in childhood. Cutaneous carcinomas in situ and invasive squamous cell carcinomas develop in about half of patients during the third or fourth decade of life. Case report: An 11-year-old boy monitored in pediatrics due to the suspicion of imperfect osteogenesis (IO) and obesity. The patient was referred to dermatology department because he had multiple papules (over 100) with warty surface, of 0.30.4 cm diameter, with skin color; located on his face (forehead, supralabial, and cheeks), hands and flexures of both wrists. Skin biopsy of one of the lesions located in his face, revealed hyperkeratosis without acanthotic epidermis. Vacuolar cells were presented in the upper stratum malpighii and granular layer. The study by HPV PCR of one of the lesions was positive for HPV5. With these results, the diagnosis of EV was performed. The main treatment is a regular monitoring for an early diagnosis of possible skin tumors, insisting on a very strict sunscreen. Our patient started treatment with topical retinoid.
Fatal dilated cardiomyopathy in a patient with recessive dystrophic epidermolysis bullosa Alexa R. Shipman, MBBCh, Birmingham Children’s Hospital, Birmingham, United Kingdom; Celia Moss, MBBCh, Birmingham Children’s Hospital, Birmingham, United Kingdom; Ashish Chickermane, MBBCh, Birmingham Children’s Hospital, Birmingham, United States; Fiona Browne, MBBCh, Birmingham Children’s Hospital, Birmingham, United Kingdom We present a 14-year-old boy with recessive dystrophic epidermolysis bullosa (RDEB) complicated by fatal cardiomyopathy. Epidermolysis bullosa is a severe blistering genodermatosis. RDEB-generalized severe subtype is characterized by extensive skin blistering with mucosal involvement, scarring, poor dentition and malnutrition. Cardiomyopathy is a rare but recognized complication. Our patient was born to unrelated Indian parents. Extensive skin loss and fragility was noted at birth, along with atrophic scarring and mucosal involvement. He was referred to the national epidermolysis bullosa service for investigation. Skin biopsy showed dermoepidermal junction split, and indirect immunofluorescence showed absent collagen 7. Mutation analysis confirmed a homozygous, nonsense mutation Q251X in exon 6 of the COL7A1 gene, confirming the diagnosis of RDEB. Both parents were heterozygous carriers. Throughout his life he had severe, widespread skin damage. He was iron, selenium and zinc deficient from infancy, despite supplementation and regular transfusions. Esophagogastric erosions resulted in dysphagia, scarring and stricturing necessitating repeated esophageal dilatations and eventual gastrostomy feeding. Within 6 months of gastrostomy insertion he presented in acute respiratory distress. Cardiomegaly and pulmonary edema were evident on chest radiograph. Cardiac echocardiogram showed a dilated left ventricle (LV) with impaired systolic function at 12% (previous ECHOs normal). Viral cardiomyopathy screens were negative. He failed to respond to medical management with angiotensin converting enzyme inhibitors, inotropes and diuretics and passed away within a month of presentation, at the age of 14. Dilated cardiomyopathy is a documented risk in RDEB, with a 4.5% cumulative risk by age of 20 years. This increases to 18.86% by the age of 35 in patients that have concomitant renal failure. In at least 30% of patients the outcome is fatal. The etiology of cardiomyopathy in EB is uncertain. Hypotheses include micronutrient deficiency (carnitine, selenium), drugs, amyloidosis or chronic iron-overload. Our patient was both carnitine and selenium deficient and had become transfusion-dependent. We were unable to establish a precise cause for his cardiomyopathy but present this case to emphasize the risk of cardiomyopathy in EB patients and the need for regular routine ECHOs.
Conclusion: We present a case of a very uncommon genodermatosis which is the EV. In the literature review we found no association between IO and EV, however, it is known that mutation of the IO is in chromosome 17q21.3-q22 and the EV’s mutation is in 17q25. Genetic studies are needed in this patient but the location at the same locus in both entities could explain its coexistence. Commercial support: None identified.
Commercial support: None identified.
876 Familiar pachyonychia congenita due to p.Met88Arg mutation in the KRT17 gene Ana M. Victoria Martınez, MD, Consorci Hospital General Universitari Valencia, Valencia, Spain; Laura Cubells Sanchez, MD, Consorci Hospital General Universitari Valencia, Valencia, Spain; M. Teresa Rico Fernandez, MD, Consorci Hospital General Universitari Valencia, Valencia, Spain; Lorena Martınez Leborans, MD, Consorci Hospital General Universitari Valencia, Valencia, Spain; Raquel Rodrıguez L opez, MD, Consorci Hospital General Universitari Valencia, Valencia, Spain; Juan J. Vilata Corell, PhD, Consorci Hospital General Universitari Valencia, Valencia, Spain; Vicente Oliver Martınez, PhD, Consorci Hospital General Universitari Valencia, Valencia, Spain Pachyonychia congenita (PC) is a group of autosomal dominant, very rare keratinizing disorders, caused by a mutation in one of 5 keratin genes KRT6A, KRT6B, KRT6C, KRT16, and KRT17. We present a case of two women of the same family with diagnosis of PC. The first patient is a 32-year-old Spanish Caucasian woman who had a history of subcutaneous yellow nodules with a widespread distribution, especially in trunk and arms, since she was 15 years old. She also had plantar hyperkeratosis since childhood and congenital thickened toenails and fingernails. Her aunt, a woman of 56 years, had similar nail dystrophy, plantar hyperkeratosis and similar history of developing multiple cyst. Histologic examination of cysts showed that were steatocystomas. Patients knew the family nature of this alteration, affecting several members of their family over five generations, with a variable severity of disease manifestations. The pedigree of the family was studied and showed an autosomal dominant mode of inheritance. Genetic analysis of the proband and her aunt identified a heterozygous c.263T [ G (p.Met88Arg) mutation in the KRT17 gene, an infrequent mutation reported in PC-17, that, from our knowledge, has just been previously described in one family. The most common clinical findings in PC are painful, palmoplantar keratoderma and nail dystrophy. Other diagnostic findings associated are follicular hyperkeratosis, leukokeratosis, cysts, hoarseness, hyperhidrosis and natal teeth. During the first year of life, dystrophy of the fingernails and toenails occurs in most of the affected infants, providing an initial clue. By 5 years of age, plantar keratoderma is seen in most children. Traditionally, two sub-types of PC have been described: PC-1 (JadassohneLewandowsky type), caused by KRT6a or KRT16 mutations, associated with oral leucokeratosis and palmoplantar keratoderma, and PC-2 (JacksoneLawler type) resulting from KRT6b or KRT17 mutations, with neonatal teeth, pili torti and multiple cysts. However, recent case reports and case series have reported overlapping clinical features of PC-1 and PC-2 and the nomenclature has recently been revised based on the molecular genetic data; for example, this family with mutations in KRT17 should be named PC-K17. In conclusion, individuals presenting symptoms of PC should undergo genetic analysis for mutations in the five known PC genes. Correct molecular diagnosis is important to aid appropriate genetic counselling and patient care. Commercial support: None identified.
AB106
J AM ACAD DERMATOL
1408 Granulomatous skin involvement in a patient with an unusual NOD2 mutation Ifedayo O. Kuye, Harvard Medical School, Boston, MA, United States; Morayo Adisa, MD, Massachusetts General Hospital, Boston, MA, United States; Rosalynn M. Nazarian, MD, Massachusetts General Hospital, Boston, MA, United States; Sheila L. Arvikar, MD, Massachusetts General Hospital, Boston, MA, United States; Gideon P. Smith, MD, PhD, Massachusetts General Hospital, Boston, MA, United States A 54-year-old male on ustekinumab for a NOD2-associated inflammatory disorder with uveitis (with an unusual heterozygous c.1799A [ C(E600A) mutation), was seen for bilateral lower extremity swelling and pain. The patient reported a year-long history of pain in his legs, without overlying skin changes. The pain worsened five months ago and was accompanied by overlying skin erythema. He was initially treated for cellulitis with amoxicillin without improvement. A skin biopsy subsequently showed focal septal panniculitis consistent with erythema nodosum. He responded somewhat to prednisone taper, but had worsening below 10 mg daily. He also failed SSKI and NSAIDs. He had worsening pain necessitating use of a wheelchair and presented to us for a second opinion. On physical exam, the patient had lower leg edema with decreased hair growth on affected areas. There were no nodules or discrete patches of erythema, but there was severe tenderness to mild touch. Given his clinical presentation, we initially felt that the erythema nodosum may have resolved and that he was now presenting with pain secondary to lipodermatosclerosis. The patient was treated with colchicine for the possibility of residual inflammation, with excellent clinical response. However, the patient developed transaminitis, and colchicine dose was stopped. He had no response to either hydroxychloroquine or dapsone. Given his pain out of proportion to the physical findings a rebiopsy of the leg was then performed showing septal fibrosis with noncaseating microgranulomas, lipophages, and focal lipo-membranous changes in the subcutaneous fat. The symptoms thus seemed more consistent with granulomas secondary to his Blau-spectrum disease rather than erythema nodosum or lipodermatosclerosis. The patient is currently being managed with intralesional kenalog with good response. Given that this NOD2 mutation was previously described in the setting of uveitis without skin involvement, this report not only presents a case of an unusual genetic form of a rare condition, but it also demonstrates skin involvement in a subtype where cutaneous involvement had not been reported. In addition, the type and presentation of the skin involvement is different from that normally found in classic Blau Syndrome, and was misdiagnosed as erythema nodosum. Finally, we report response to colchicine, although ultimately not tolerated by this patient. Commercial support: None identified.
MAY 2015