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Congenital Erythropoietic Porphyria DERMATOLOGICA SINICA 30 (2012) 62e65 Contents lists available at SciVerse ScienceDirect Dermatologica Sinica journal homepage: http://www.derm-sinica.com CASE REPORT Congenital erythropoietic porphyria Wen-Hao Lee 1, Wei-Chun Tai 1, Po-Yuan Wu 1,2,* 1 Department of Dermatology, China Medical University Hospital, Taichung, Taiwan 2 Department of Dermatology, China Medical University, Taichung, Taiwan article info abstract Article history: Congenital erythropoietic porphyria (CEP), or “Günther disease”, is a rare variant of porphyria. It is an Received: Mar 7, 2011 autosomal recessive disease caused by deficient uroporphyrinogen III synthase (URO-III-synthase), the Revised: Apr 27, 2011 fourth enzyme in the heme biosynthetic pathway. We herein report a case of a man with the typical Accepted: Jun 7, 2011 clinical presentations of hyper- and hypo-pigmentation and blister formation over sun-exposed areas, mutilation of the fingers, dark-purple urine, and erythrodontia with pinkish fluorescence under a Wood’s Keywords: lamp. The diagnosis was confirmed by decreased activity of URO-III-synthase in red blood cells (RBC) and congenital erythropoietic porphyria a porphyrin profile compatible with CEP. Günther disease Copyright Ó 2012, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved. Introduction areas which required sun-protection. When he was 1 year old, his urine color changed gradually from red-purple to dark-purple. At Porphyrias are a diverse group of inherited or acquired heme that time, porphyria was already the impression, but no further biosynthesis disorders. Each sub-type results from deficient activity studies were performed. His teeth became brownish (eryth- of a specific enzyme in the heme biosynthetic pathway. Congenital rodontia) while he was in elementary school, and hypertrichosis erythropoietic porphyria (CEP) is a rare sub-group with the most developed with irregular hypo- and hyper-pigmentation over severe photosensitivity and mutilation.1 Typical features of CEP also unprotected skin areas upon reaching puberty. include erythrodontia and dark-purple urine. The diagnosis is made Since his high school years, the patient suffered from frequent by porphyria profile study and decreased relative enzyme activity. malaise and anemia with hemoglobin fluctuating between 8 and Here we present a male CEP patient with typical clinical 11 g/dL. Eight years before visiting our department, virus-associated presentations. hemophagocytic syndrome with pancytopenia caused his hemo- globin to drop from 10 to 3.5 g/dL and he presented with severe weakness and headache, with splenomegaly proven by sonography. Case report Furthermore, he suffered transfusion-dependent hemolytic anemia requiring monthly transfusions of 1000 mL of whole blood to A 28-year-old male visited our dermatology department 3 years maintain Hb > 8 g/dL 3 years before our first inspection. At this time previously due to severe sun-burn after biking. A physical exami- his serum ferritin level was up to 6721 ng/mL. nation showed extreme scarring with multiple milia formation, On consultation, his porphyrin profile was analyzed through dyspigmentation (Figures 1A and 1B), and loss of acral tissues his stool and urine using high performance liquid chromatography (mutilation of the fingers) (Figures 1C and 1D) over frequently and spectrofluorometry (Table 1). The urine study showed exposed skin areas (i.e., the face, forearms, hands and shins). He extremely increased levels of uroporphyrin isomer I and cop- also had brownish teeth (Figures 2A and 2B), dark-purple urine roporphyrin isomer I, with a lesser degree of elevation in hepta-, (Figures 2C and 2D), and icteric sclera emitting pinkish fluorescence hexa- and pentacarboxylporphyrin (7-, 6- and 5-COOH- under Wood’s light detection. Porphyria was diagnosed, with porphyrin). The stool profile also showed extremely high levels of consideration of CEP as the possible sub-type. coproporphyrin I with an isomer III/I ratio of 0.1 and increased The patient had a healthy younger brother, no family history of uroporphyrin I, although isomer III was almost undetectable. porphyria and no consanguinity. After birth, he began to get Moreover, the level of 5-COOH-porphyrin isomer III was much sunburned easily, with noticeable blister formation on exposed higher than isomer I, and despite no elevation in protoporphyrins, * isocoproporphyrin was mildly elevated in the stool specimen. All Corresponding author. Po-Yuan Wu, 2 Yuh-Der Road, Taichung City 40447, fi Taiwan. Tel.: þ886 4 22052121x4437; fax: þ886 4 22076506. of these ndings were compatible with the clinical impression E-mail address: [email protected] (P.-Y. Wu). of CEP. 1027-8117/$ e see front matter Copyright Ó 2012, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.dsi.2011.09.012 W.-H. Lee et al. / Dermatologica Sinica 30 (2012) 62e65 63 Figure 1 (A) Multiple milia around the nose with icteric sclera and hyperpigmented face; (B) obvious dyspigmentation over the shin; (C) severe mutilation of the fingers with scarring and hypertrichosis over sun-exposed areas; (D) close-up view of the mutilation of the fingers. The activity of URO-III-synthase in red blood cells (RBC) was also porphyrias, and squamous cell carcinomas over the distal ends have evaluated by URO-III-synthase quasi coupled enzyme assay, and been reported with resorption.5 showed 15 relative units, much lower than the lower limit of 75 Large amounts of pathogenic porphyrins are excreted in stools units of the reference range (Table 1). Given the clinical presenta- and urine, which make the urine dark-purple with pinkish fluo- tion, porphyrin profile, and documented decrease in specific rescence. Similarly, red-brownish teeth with porphyrins also emit enzyme activity, CEP was the final diagnosis. pinkish fluorescence under a Wood’s lamp (erythrodontia), which is The patient did not accept transplantation due to fears of a very special feature or even pathognomonic2 of CEP. In the bones, possible complications, and avoided sunlight as the only treatment. fragility and resorption of terminal phalanges may develop.1,3,4,6 Patients with the severe form will have marked hemolytic Discussion anemia and may be transfusion-dependent for life.4 Secondary splenomegaly may also develop due to the increased uptake of Porphyrias are a group of disorders related to defects of enzymes abnormal erythrocytes and this, in turn, may exacerbate the processing the production of heme. Although traditionally catego- anemia, leukopenia, and thrombocytopenia.6,7 rized as hepatic or erythropoietic forms, they are also classified into In non-acute porphyria, both early onset CEP and erythropoietic dermatologic-dominant “non-acute” forms, in contrast to life- protoporphyria are found, although CEP is found earlier than threatening “acute” forms that feature neurologic symptoms erythropoietic protoporphyria. Clinically, swelling erythema with (Figure 3).2 minor blister formation is seen in erythropoietic protoporphyria, CEP is a very rare disease with only approximately 200 patients without pink-florescent urine. CEP may be similar with hepato- reported worldwide.1,2 The first sign of CEP is often during a child’s erythropoietic porphyria in mutilations, but without splenomegaly 1st month, with pinkish or brown porphyrin staining of diapers. or elevated ferritin.1,2,4,8 Porphyria cutaneous tarda is adult onset, Severe photo-sensitivity and easy-blister formation after exposure occurs without erythrodontia, and has a better prognosis than CEP. to sunlight then develop in patients with severe forms. Recurrent URO-III-synthase normally catalyzes hydroxymethylbilane to wound formation, with secondary bacterial infection, may induce uroporphyrinogen III, which is the real physiologic intermediate.2,7 milia formation, disfigurement, and even auto-amputation (muti- The deficient activity of URO-III-synthase directly leads to accu- lation) over the digital tips, nose, or ears, while corneal scarring can mulated hydroxymethylbilane that is mostly non-enzymatically lead to blindness.3,4 CEP is the most mutilating type of the converted to uroporphyrinogen I. This is then catalyzed by 64 W.-H. Lee et al. / Dermatologica Sinica 30 (2012) 62e65 Figure 2 (A) Brownish teeth with; (B) pinkish fluorescence under Wood’s light detection; (C) the dark-purple urine of our patient (left) compared with a normal person’s light- yellow urine (right); (D) pinkish fluorescence under Wood’s light detection (left) compared with the normal sample (right). uroporphyrinogen decarboxylase to form hepta-, hexa- and pen- stools. Since the next enzyme, coproporphyrinogen oxidase, is only tacarboxylporphyrinogen I, and ultimately, coproporphyrinogen I. specific to isomer III, coproporphyrinogen I is not catalyzed This accumulates in the bone marrow (normoblasts and reticulo- further.7,9 cytes), erythrocytes, plasma, bones, and teeth and undergoes auto- The urine and stool studies of our patient showed extremely oxidation to the corresponding porphyrins excreted in urine and increased levels of uroporphyrin and coproporphyrin, with lesser elevated hepta-, hexa- and pentacarboxyl porphyrins, as in other case presentations. In addition, they were all isomer I dominant, Table 1 Porphyrin profiles reports in urine and stool specimens and uroporphyri- although levels of isomer III were also increased. Extremely elevated nogen III synthase activity in RBC. levels of uroporphyrin isomer I and coproporphyrin
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