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Porphyria cutanea tarda: A novel mutation
Pediatric Hematology Oncology Journal xxx (2016) 1e2
Contents lists available at ScienceDirect
Pediatric Hematology Oncology Journal journal homepage: https://www.elsevier.com/journals/pediatrichematology-oncology-journal/
Porphyria cutanea tarda: A novel mutation* Rajesh Patil a, *, Bhavna Dhingra a, Dinesh Asati b, Garima Goel c, Ujjawal Khurana c, Girish Chandra Bhatt a a
Department of Pediatrics, All India Institute of Medical Sciences, Bhopal, India Department of Dermatology, All India Institute of Medical Sciences, Bhopal, India c Department of Pathology, All India Institute of Medical Sciences, Bhopal, India b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 March 2016 Accepted 14 April 2016 Available online xxx
A 5 year old child with waxing and waning vesicobullous lesions on exposed parts since two years. Blood porphyrin levels were increased and Woods lamp revealed erythrodontia. DNA analysis showed the child was homozygous and both parents were heterozygous for a novel pathogenic mutation V256M in uroporphyrinogen decarboxylase gene, thus diagnosed as type II recessive form of porphyria cutanea tarda. The child responded to sunscreens and antioxidants. © 2016 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
Keywords: Porphyria Mutation Uroporphyrinogen decarboxylase
1. Introduction Porphyrias are a group of disorder characterized by defect in heme production, resulting in accumulation of toxic heme precursors. Skin manifestations are common like photosensitivity, painful burning, vasiculo-bullous lesions, healing with scar formation [1]. Porphyria cutanea tarda (PCT) in children is a rare biochemical derangement resulting into various dermatological manifestations. The spectrum of the disease depends upon the quantitative deficient activity of the heme synthetic enzyme Uroporphyrinogen Decarboxylase (UROD). The UROD gene has been mapped on chromosome 1p34 [2]. More than seventy mutations have been reported so far on this gene. Approximately 80% of the PCT are sporadic (type I). Familial form of PCT (type II) is rare. Most of the cases of PCT type II are autosomal dominant but very rarely autosomal recessive forms are reported. Sporadic PCT presents in fourth decade while familial forms manifest at any age. Biallelic mutations cause severe symptoms that appear early [1]. 2. Case We report a case of a five years old male child, born to a nonconsanguinous marriage, with complaints of blisters on the sun * We state that all authors have contributed to manuscript in significant way and agreed on manuscript content. * Corresponding author. Department of Pediatrics, All India Institute of Medical Sciences, Saket Nagar, Bhopal, MP 462020, India. Tel.: þ91 9826282850. E-mail address: [email protected] (R. Patil). Peer review under responsibility of Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics
exposed body parts (face, V of chest, both hands and feet) since last three years with waxing and waning course. Different stages of lesions were present at the same time and there were scars from healing of previous lesions along-with hypopigmented and hyperpigmented macules. He had delayed healing of wounds even after minor scratches (Fig. 1). Hypertrichosis was observed over temporal and malar area of the face, plethora of the central face, neck and upper chest was noted (Fig. 2). The child also had erosion and brownish discoloration of multiple teeth; Rest of the general physical and systemic examination was unremarkable. There was no history of other chronic illness and no history of similar complaints in any of the family members. Clinically the child was suspected to be having cutaneous porphyria. Complete blood count and peripheral smear were unremarkable except for mild normocytic anaemia, fluorescence test for uroporphobilinogen in urine was positive; biopsy taken from the lesion showed positivity towards periodic acid Schiff's (PAS) staining, test for porphyrin in blood showed increase in total porphyrin. Liver function tests revealed Aspartate aminotransferase (AST) 31 U/L, Alanine aminotransferase (ALT) 41 U/L, Alkaline phosphate (ALP) 223 U/L, Total serum bilirubin 0.4 mg/dl (direct 0.1 and indirect 0.3), total protein 8 mg/dl with a normal albumin:globulin ratio. On woods lamp examination he was found to have erythrodontia. Serology for hepatitis B and C were negative. Blood sample from the child and both parents and were sent for DNA and mutation analysis which revealed that the child was homozygous and both parents were heterozygous for a novel mutation V256M in the UROD gene. This mutation has not been
http://dx.doi.org/10.1016/j.phoj.2016.04.001 2468-1245/© 2016 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Patil R, et al., Porphyria cutanea tarda: A novel mutation, Pediatric Hematology Oncology Journal (2016), http://dx.doi.org/10.1016/j.phoj.2016.04.001
2
R. Patil et al. / Pediatric Hematology Oncology Journal xxx (2016) 1e2
Fig. 1. Showing multiple vesicobullous lesions on the hands with scar formation.
porphyrins are responsible for most of the symptoms [1,2]. Clinically, PCT in child presents as blisters, hypo or hyperpigmented scars on sun exposed body parts, increase in facial hairs and fragility of skin, tooth discoloration and mild anaemia [1e3]. In the present case the child had most of these features. Family members may be symptomatic or asymptomatic depending upon the level of deficiency of the UROD enzyme. It has been shown that PCT is associated with hemochromatosis and hepatitis C. Increased incidence of liver neoplasm has been observed in patients of PCT [4]. PCT is a multifactorial disease; alcohol, exogenous hormone, iron overload and human immunodeficiency virus (HIV) are associated [1]. Our patient had none of these findings. Clinically suspected PCT can be confirmed by UROD activity, porphyrin levels, urofluorescence test, skin biopsy and mutation analysis [1,5]. Child was homozygous for the mutation V256M and both parents were heterozygous for the same mutation explaining autosomal recessive inheritance. In the present case, none of the family members were symptomatic, except the index case. This child is the only issue of his parents and as the family was not complete so antenatal diagnosis was suggested to the parents. Few treatment modalities for PCT have been described including antioxidants, phlebotomy and low dose chloroquine/hydroxychloroquine [6e8]. In the present case, the child was prescribed antioxidants, avoidance of sun exposure and sun screen lotions which resulted in significant improvement in the skin lesions. Such patients need to be in long term follow-up to watch for any associated conditions and complications. Support and funding None. Conflicts of interest None.
Fig. 2. Showing hypertrichosis, plethora over temporal and malar area on face.
previously reported. Mutation was found to be pathogenic/disease causing using Mutation taster and Polyphen databases. UROD enzyme activity estimation could not be done in our setup due to financial and logistic constraints. He was diagnosed as having type II (familial) recessive form of PCT. The child was prescribed regular use of sun screen lotion, beta carotenoids and vit E with avoidance of exposure to direct sunlight. After 3 months, the cutaneous lesions of the child had markedly improved and there were no fresh lesions. The child continues to be in follow-up at 12 months and there are no fresh lesions, no anemia and the liver function is normal. We took written informed consent from the parents for publication of images and reports concerned to the child. 3. Discussion Homozygous conditions of PCT are very rare and present early in childhood with much symptomatology. Quantitative deficiency of UROD enzyme leads to overproduction of 4e8 carboxyl group substituents in heme synthetic pathway [1]. These products get deposited in skin, liver and accumulate in plasma. Photo-oxidized
Acknowledgement Mount Sinai Genetics Testing laboratory. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L, Levy place, Box 1497, New York, NY 10029-6574. References [1] Mary H, Ali A, Suzanne T, Silvia T, Dawn M, Jennifer L. Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Int J Dermatol 2013;52:1464e80. [2] Bygum A, Christiansen L, Petersen N. Familial and sporadic porphyria cutanea tarda: clinical, biochemical and genetic features with emphasis on iron status. Acta Derm Venereol 2003;83(2):115e20. [3] Elder G. The cutaneous porphyrias. Semin Dermatol 1990;9(1):63e9. [4] Lim W, Mascaro JM. The porphyrias and hepatocellular carcinoma. Dermatol Clin 1995;13(1):135e42. [5] Maynard B, Peters M. Histologic and immunofluorescence study of cutaneous porphyrias. J Cutan Pathol 1992;19:40. [6] Singal A, Kormos C, Lee C, Sadagoparamanujam M, Grady J, Freeman Jr H, et al. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol 2012;10: 1402. [7] Epstein H, Redeker G. Porphyria cutanea tarda. A study of the effect of phlebotomy. N Engl J Med 1968;279:1301. [8] Sarkany R. The management of porphyria cutanea tarda. Clin Exp Dermatol 2001;26:225.
Please cite this article in press as: Patil R, et al., Porphyria cutanea tarda: A novel mutation, Pediatric Hematology Oncology Journal (2016), http://dx.doi.org/10.1016/j.phoj.2016.04.001
Contents lists available at ScienceDirect
Pediatric Hematology Oncology Journal journal homepage: https://www.elsevier.com/journals/pediatrichematology-oncology-journal/
Porphyria cutanea tarda: A novel mutation* Rajesh Patil a, *, Bhavna Dhingra a, Dinesh Asati b, Garima Goel c, Ujjawal Khurana c, Girish Chandra Bhatt a a
Department of Pediatrics, All India Institute of Medical Sciences, Bhopal, India Department of Dermatology, All India Institute of Medical Sciences, Bhopal, India c Department of Pathology, All India Institute of Medical Sciences, Bhopal, India b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 March 2016 Accepted 14 April 2016 Available online xxx
A 5 year old child with waxing and waning vesicobullous lesions on exposed parts since two years. Blood porphyrin levels were increased and Woods lamp revealed erythrodontia. DNA analysis showed the child was homozygous and both parents were heterozygous for a novel pathogenic mutation V256M in uroporphyrinogen decarboxylase gene, thus diagnosed as type II recessive form of porphyria cutanea tarda. The child responded to sunscreens and antioxidants. © 2016 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
Keywords: Porphyria Mutation Uroporphyrinogen decarboxylase
1. Introduction Porphyrias are a group of disorder characterized by defect in heme production, resulting in accumulation of toxic heme precursors. Skin manifestations are common like photosensitivity, painful burning, vasiculo-bullous lesions, healing with scar formation [1]. Porphyria cutanea tarda (PCT) in children is a rare biochemical derangement resulting into various dermatological manifestations. The spectrum of the disease depends upon the quantitative deficient activity of the heme synthetic enzyme Uroporphyrinogen Decarboxylase (UROD). The UROD gene has been mapped on chromosome 1p34 [2]. More than seventy mutations have been reported so far on this gene. Approximately 80% of the PCT are sporadic (type I). Familial form of PCT (type II) is rare. Most of the cases of PCT type II are autosomal dominant but very rarely autosomal recessive forms are reported. Sporadic PCT presents in fourth decade while familial forms manifest at any age. Biallelic mutations cause severe symptoms that appear early [1]. 2. Case We report a case of a five years old male child, born to a nonconsanguinous marriage, with complaints of blisters on the sun * We state that all authors have contributed to manuscript in significant way and agreed on manuscript content. * Corresponding author. Department of Pediatrics, All India Institute of Medical Sciences, Saket Nagar, Bhopal, MP 462020, India. Tel.: þ91 9826282850. E-mail address: [email protected] (R. Patil). Peer review under responsibility of Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics
exposed body parts (face, V of chest, both hands and feet) since last three years with waxing and waning course. Different stages of lesions were present at the same time and there were scars from healing of previous lesions along-with hypopigmented and hyperpigmented macules. He had delayed healing of wounds even after minor scratches (Fig. 1). Hypertrichosis was observed over temporal and malar area of the face, plethora of the central face, neck and upper chest was noted (Fig. 2). The child also had erosion and brownish discoloration of multiple teeth; Rest of the general physical and systemic examination was unremarkable. There was no history of other chronic illness and no history of similar complaints in any of the family members. Clinically the child was suspected to be having cutaneous porphyria. Complete blood count and peripheral smear were unremarkable except for mild normocytic anaemia, fluorescence test for uroporphobilinogen in urine was positive; biopsy taken from the lesion showed positivity towards periodic acid Schiff's (PAS) staining, test for porphyrin in blood showed increase in total porphyrin. Liver function tests revealed Aspartate aminotransferase (AST) 31 U/L, Alanine aminotransferase (ALT) 41 U/L, Alkaline phosphate (ALP) 223 U/L, Total serum bilirubin 0.4 mg/dl (direct 0.1 and indirect 0.3), total protein 8 mg/dl with a normal albumin:globulin ratio. On woods lamp examination he was found to have erythrodontia. Serology for hepatitis B and C were negative. Blood sample from the child and both parents and were sent for DNA and mutation analysis which revealed that the child was homozygous and both parents were heterozygous for a novel mutation V256M in the UROD gene. This mutation has not been
http://dx.doi.org/10.1016/j.phoj.2016.04.001 2468-1245/© 2016 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Patil R, et al., Porphyria cutanea tarda: A novel mutation, Pediatric Hematology Oncology Journal (2016), http://dx.doi.org/10.1016/j.phoj.2016.04.001
2
R. Patil et al. / Pediatric Hematology Oncology Journal xxx (2016) 1e2
Fig. 1. Showing multiple vesicobullous lesions on the hands with scar formation.
porphyrins are responsible for most of the symptoms [1,2]. Clinically, PCT in child presents as blisters, hypo or hyperpigmented scars on sun exposed body parts, increase in facial hairs and fragility of skin, tooth discoloration and mild anaemia [1e3]. In the present case the child had most of these features. Family members may be symptomatic or asymptomatic depending upon the level of deficiency of the UROD enzyme. It has been shown that PCT is associated with hemochromatosis and hepatitis C. Increased incidence of liver neoplasm has been observed in patients of PCT [4]. PCT is a multifactorial disease; alcohol, exogenous hormone, iron overload and human immunodeficiency virus (HIV) are associated [1]. Our patient had none of these findings. Clinically suspected PCT can be confirmed by UROD activity, porphyrin levels, urofluorescence test, skin biopsy and mutation analysis [1,5]. Child was homozygous for the mutation V256M and both parents were heterozygous for the same mutation explaining autosomal recessive inheritance. In the present case, none of the family members were symptomatic, except the index case. This child is the only issue of his parents and as the family was not complete so antenatal diagnosis was suggested to the parents. Few treatment modalities for PCT have been described including antioxidants, phlebotomy and low dose chloroquine/hydroxychloroquine [6e8]. In the present case, the child was prescribed antioxidants, avoidance of sun exposure and sun screen lotions which resulted in significant improvement in the skin lesions. Such patients need to be in long term follow-up to watch for any associated conditions and complications. Support and funding None. Conflicts of interest None.
Fig. 2. Showing hypertrichosis, plethora over temporal and malar area on face.
previously reported. Mutation was found to be pathogenic/disease causing using Mutation taster and Polyphen databases. UROD enzyme activity estimation could not be done in our setup due to financial and logistic constraints. He was diagnosed as having type II (familial) recessive form of PCT. The child was prescribed regular use of sun screen lotion, beta carotenoids and vit E with avoidance of exposure to direct sunlight. After 3 months, the cutaneous lesions of the child had markedly improved and there were no fresh lesions. The child continues to be in follow-up at 12 months and there are no fresh lesions, no anemia and the liver function is normal. We took written informed consent from the parents for publication of images and reports concerned to the child. 3. Discussion Homozygous conditions of PCT are very rare and present early in childhood with much symptomatology. Quantitative deficiency of UROD enzyme leads to overproduction of 4e8 carboxyl group substituents in heme synthetic pathway [1]. These products get deposited in skin, liver and accumulate in plasma. Photo-oxidized
Acknowledgement Mount Sinai Genetics Testing laboratory. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L, Levy place, Box 1497, New York, NY 10029-6574. References [1] Mary H, Ali A, Suzanne T, Silvia T, Dawn M, Jennifer L. Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Int J Dermatol 2013;52:1464e80. [2] Bygum A, Christiansen L, Petersen N. Familial and sporadic porphyria cutanea tarda: clinical, biochemical and genetic features with emphasis on iron status. Acta Derm Venereol 2003;83(2):115e20. [3] Elder G. The cutaneous porphyrias. Semin Dermatol 1990;9(1):63e9. [4] Lim W, Mascaro JM. The porphyrias and hepatocellular carcinoma. Dermatol Clin 1995;13(1):135e42. [5] Maynard B, Peters M. Histologic and immunofluorescence study of cutaneous porphyrias. J Cutan Pathol 1992;19:40. [6] Singal A, Kormos C, Lee C, Sadagoparamanujam M, Grady J, Freeman Jr H, et al. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol 2012;10: 1402. [7] Epstein H, Redeker G. Porphyria cutanea tarda. A study of the effect of phlebotomy. N Engl J Med 1968;279:1301. [8] Sarkany R. The management of porphyria cutanea tarda. Clin Exp Dermatol 2001;26:225.
Please cite this article in press as: Patil R, et al., Porphyria cutanea tarda: A novel mutation, Pediatric Hematology Oncology Journal (2016), http://dx.doi.org/10.1016/j.phoj.2016.04.001