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Congenital erythropoietic porphyria: Clinical, biochemical, and enzymatic profile of a severely affected infant
Congenital erythropoietic porphyria: Clinical, biochemical, and enzymatic profile of a severely affected infant Jun-ling Huang, PhD, a Edith Zaider, MS, b Philip Roth, MD, PhD, c Olga Garcia, MD, c Shoshannah Pollack, MD, d and Maureen B. Poh-Fitzpatrick, M D b Valhalla, New York Ci~,
and Bronx, New York Blistering of light-exposed skin, pink-stained fluorescing diapers, and fluorescing peripheral erythrocytes led to diagnosis of congenital porphyria in an infant born to consanguineous parents. Although massive coproporphyrinuria and coproporphyrinemia initially suggested a coproporphyrinogen oxidase deficiency disorder, excess porphyrins were chiefly of the isomer I series, implicating a uroporphyrinogen llI synthase defect. Congenital erythropoietic porphyria was confirmed by demonstration of a profound defect in the activity of the infant's uroporphyrinogen HI synthase (4% of the mean value for nine normal controls) and in both parents at approximately 50% of the mean normal activity. Coinheritance of gene defects for either hereditary coproporphyria or erythropoietic protoporphyria in addition to those for congenital erythropoietic porphyria was excluded by demonstrating normal activities of both coproporphyrinogen oxidase and ferrochelatase in the infant. The complicated perinatal and postnatal clinical course and biochemical and enzyme assay data for the infant and his parents are described. (J AM ACAODERMATOL1996;34:924-7.) Congenital erythropoietic porphyria (CEP), a rare autosomal recessive disorder of heme synthesis, resuits from partial deficiency of uroporphyrinogen HI synthase (URO-S, formerly termed uroporphyrinogen HI cosynthase) activity that typically leads to accumulation of porphyrins of the isomer I type.l-3 Uroporphyrin I is usually the predominant urinary and plasma metabolite, whereas coproporphyrin I predominates in feces, and increased uro-, coproand protoporphyrins may all occur in erythrocytes. CEP is clinically manifested by cutaneous photosensitivity and hemolytic anemia of varying severities and their complications. Onset occurs most often in infancy but occasionally in adult life. From the Department of Dermatology, New York Medical College, Valhalla,a the Department of Dermatology, Columbia University College of Physicians and Surgeons, New York City,t' the Division of Neonatology, Department of Pediatrics,Cand Division of Dermatology, Department of Medicine, d Montefiore Medical Center, Albert Einstein College of Medicine, Bronx. Supported by research grant ROI AR18549 from the National Institute for Arthritis, Musculoskeletal, and Skin Diseases, DHHS, Bethesda, Maryland. Reprint requests: Maureen B. Poh-Fitzpatrick, MD, Columbia/St. Luke's-Roosevelt, 432 W. 58th St., AJA 206, New York, NY 10019. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0 16/4/69109
924
We report a case of porphyria, diagnosed shortly after birth, in which the predominant urinary, fecal, plasma, and erythrocyte porphyrins were coproporphyrin I. The stormy clinical course experienced by this infant and the laboratory investigations of the child and his parents, indicating a diagnosis of CEP, are described. CASE R E P O R T
A son was born to Hispanic parents who were first cousins and had one previous child, who was healthy. There was no family history of photosensitivity or of porphyria. The infant was delivered at term; meconiumstained amniotic fluid was noted. Shortly after birth, respiratory distress, temperature instability, bloody urine and stool, and jaundice developed. Physical examination was notable for tachypnea, tachycardia, a soft systolic murmur, and hepatosplenomegaly. Pertinent laboratory abnormalities included a hematocrit value of 32.9% with 4.2% reticulocytes, 76,000 platelets per cubic millimeter, serum total bilirubin of 9.8 mg/di with a direct component of 6.8 mg/dl, and prolonged prothrombin and partial thomboplastin times. A direct Coombs' test yielded negative findings. On day 9, marked facial edema was noted; vesicles and bullae appeared on the infant's face, trunk, and extremities. A urine-soaked diaper was discolored; it fluoresced pink with Wood's light illumination. Periph-
Journal of the American Academy of Dermatology Volume 34, Number 5, Part 2
Table I.
Huang et aL
925
Total porphyrin values in urine, feces, plasma, and erythrocytes for proband and parents
Urine ~anol/mol creatinine
85,222
Feces nmol/100 g Plasma nmogL Erythrocytes nmoFL
4,492 48,195 5,874
6
10
15 2,314
-15 409
--
< - 8 2 (infants) <40 (adult females) <33 (adult males) Not established for infants <15 <890
*The upper limit for infantile urinary porphyrin excretion is estimated at the 95th percentile confidence limit of data indicating an inverse correlation between age and porphyrin excretion in children 9 months to 18 years of age. 2l Adult limits are two standard deviations above means determined by that study from our laboratory. The fecal value is from SmithKline Beecham Laboratories; normal infant reference limits are not available. Plasma and erythrocyte values were previously established in our laboratory.
eral erythrocytes were noted to fluoresce red with darkfield microscopy using blue-violet epiluminescence, leading to laboratory evaluation for a presumptive diagnosis of porphyria. Total erythrocyte and plasma porphyrin concentrations were determined as described by Piomelli,4 and PohFitzpatrick and DeI_e~, 5 respectively. A random urine sample was similarly analyzed for total porphyrin content. Urinary creatinine was measured by a method based on the Jaffe alkaline picrate reaction.6 Urinary porphyrins were fractionated by carboxyl number by thin-layer chromatography as described by Smith] Porphyrin isomer composition was determined by means of high- performance liquid chromatography as described by Lim and Peters. 8 Fecal porphyrins were quantified chromatographically by a comrnercial laboratory. Excessive excretion of porphyrins was evident in urine and feces, and both plasma and erythrocytes contained massively abnormal porphyrin content. In all specimens examined for isomer partition, the predominant porphyrin present was coproporphyrin I. In porphyrin studies of both parents, the only abnormal finding was mildly increased zinc protoporphyrin in the mother's erythrocytes, which could not be explained by either an abnormal blood lead level or iron deficiency. Neither parent excreted abnormal levels or isomer ratios of urinary porphyrins. Quantitative data are given in Tables I and II. Although large amounts of the isomer I series porphyfins suggested CEP, the stormy clinical course and overwhelming preponderance of coproporphyrins rather than uroporphyrins in all specimens led to concern that multiple gene defects encoding deficient activity in more than one of the heine biosynthetic enzymes might have been inherited, particularly those associated with hereditary coproporphyria or a variant of erythropoietic protoporphyria. Accordingly, activities of the enzymes defective in those disorders were measured in leukocytes from the patient: coproporphyrinogen oxidase as described by Guo, Lim, and Peters 9 and ferrochelatase as described by Nunn et al.m0 Activity levels for both were found to be
Table
II. Porphyrin isomer partitioning in proband's urine
I %of total Isomers
porphyrins
Ratio of I/HI
Coproporphyrin I Coproporphyrin HI Uroporphyrin I Uroporphyrin HI
75.0 3.9 11.0 0.3
19.2" 36.7
*A mean value for the ratio of coproporphyrin I/IlI previously determined in our laboratories in urine of 12 normal children ranging in age from 1.5 to 18 years is 0.4 _+ 0.222
normal. Leukocyte uroporphyrinogen HI synthase activity was measured for the infant and both parents essentially as described by Tsai, Bishop, and Desnick. ll The infant's activity was only 3.8% of a mean value estabfished for nine normal control subjects. His father and mother had 56.2% and 40.8% of the normal mean activity, respectively. These data confirmed the diagnosis of CEP. To suppress erythropoiesis and the accumulation of porphyrins, a chronic transfusion program was instituted to maintain the child's hematocrit at greater than 35%. 12 Severe hemosiderosis with extensive deposits of iron in fiver and spleen was detected by magnetic resonance imaging when the patient was 4 months old. At 6 months, deferoxmltine chelation therapy was begun in 14-day cycles at 60 mg/kg daily with a 14-day period between cycles. This resulted in reduction of serum ferritin levels from 2853 ng/ml to 1405 ng/ml over 8 months. Hepatosplenomegaly and thrombocytopenia persisted throughout the first year of life. In addition to his hematologic disease, the infant's course was complicated by anorexia, intermittent emesis, and malabsorption. At age 4 months, results of a duodenal biopsy and an upper gastrointestinal radiographic examination were normal. Although the patient initally required central total parenteral nutrition, a gastrostomy
926
Huang et al.
tube was placed for administration of a nutrient formula and cereal on which he was maintained. The patient also experienced multiple episodes of sepsis and a bemorrhagic cranial infarct during the first year of life. At 2 ~ years of age, the child is developmentally delayed. He is able to sit without assistance, is socially interactive, and is just beginning to say words. The child is kept under an amber fight-filtering film (TA-81, Madico, Saugus, Mass.) to reduce photosensitivity reactions. This practice, combined with hypertransfusion, has minimized the development of new skin lesions. He has extensive dyspigmentation and scarring of fight-exposed skin. Erythrodontia is marked in visible light. Under Wood's fight the teeth are brightly fluorescent. DISCUSSION
Congenital erythropoietic porphyria in the modem era is not uncommonly heralded by severe skin blistering that occurs after phototherapy for neonatal jaundice. 13-14 In this case, no phototherapy was given; even so, marked cutaneous photosensitivity was elicited by the ambient light of the nursery. In recent reports, cases of CEP have usually been confirmed by demonstration of uroporphyrinogen Ill synthase deficiency. Although uroporphyrin I is more often the predominant urinary metabolite in CEP, L 2 this is not the first case in which coproporphyrin I has been the greater fraction. 14-16However, the massive presence of coproporphyrin in all specimens raised the question of coexistent hereditary coproporphyria and CEP as reported by Nordmann et a1.17 In that case, the infant was also born to first cousins and presented with neonatal jaundice, hepatosplenomegaly, diffuse bleeding, thrombocytopenia, bullous skin lesions, and red urine; stunted growth and poor mental development were noted in the first year of life, as in our case. Despite the many clinical and biochemical similarities, the demonstration of normal activity of coproporphyrinogen oxidase in our case excluded that possibility. Verstraeten et al.~5 reported a case of CEP in which a severely affected infant had hydrops fetalis, hepatosplenomegaly, and anemia in utero. At birth the infant was icteric; phototherapy elicited marked photosensitivity on the first day of life. Pink urine, hypertrichosis, and fluorescing erythrocytes were noted. The infant died 24 hours after birth, exhibiting respiratory acidosis, bradycardia, and a diffuse hemorrhagic syndrome. Although enzyme assays in the infant were not done, activities of many of the heme synthetic enzymes, including those for CEP
Journal of the American Academy of Dermatology May 1996
and hereditary coproporphyria, were tested in parental specimens, revealing normal coproporphyrinogen oxidase levels but 50% reduction in normal activity for uroporphyrinogen I~ synthase for both parents. Of particular interest in reference to our case is that the infant described by Verstraeten et al. also had predominant coproporphyrin I in erythrocytes, plasma, urine, and feces. A sibling of theft patient had died in utero with similar problems. A subsequently conceived sibling of our patient was also diagnosed with CEP in utero (details to be reported separately) but died shortly after birth despite intensive care. Fourteen different mutations in the uroporphyrinogen III synthase gene have now been described in association with confirmed cases of CEP. 16' 18, 19 Some of these mutations yield greater residual activity of the encoded enzyme, conferring milder phenotypes upon their recipients, whereas other mutations encode defective enzymes with lesser activities and have been associated with more severely affected phenotypes. 1s-2° Because each of the firstcousin parents of this child are likely to be heteroallelic for the same abnormality at the locus for uroporphyrinogen HI synthase, the profoundly abnormal clinical, biochemical, and enzymatic manifestations in this case suggest that the child is homoallelic for a mutation among those linked to the most severely affected persons. The precise molecular nature of the mutant alleles encoding defective uroporphyrinogen HI synthase that are present in this family has been under study and will be separately described. We are grateful to Carolyn Raab, RN, PNP, Donna Geiss, RN, NNP, and the neonatology nursing staff of the Montefiore Medical Center for outstanding patient and family support and provision of clinical specimens; to Damaris Carriero for performing the ferrochelatase assay; and to Sergio Piomelfi, MD, for insightful scientific counsel. REFERENCES
1. KappasA, Sassa S, Galbraith RA, et al. The porphyrias. In: Stanbury JB, Wyngaarden JB, Fredickson DS, eds. The metabolic basis of inherited diseases. 6th ed. New York: McGraw-Hill, 1989;1305-65. 2. Nordmann Y, DeybachJC. Congenital erythropoieticporphyria. Sere Liver Dis 1982;2:154-63. 3. Romeo G, Levin EY. UroporphyrinogenIll cosynthase in human congenitalerythropoieticporphyria.Proc Natl Acad Sci U S A 1969;63:856-63. 4. Pi°melli S"A micr°meth°d f°r free erythr°cytep°rphyrins: the FEP test. J Lab Clin Med 1973;81:932-40. 5. Poh-FitzpatrickMB, DeLeo VA. Rates of plasma porphy-
Journal of the American Academy of Dermatology Volume 34, Number 5, Part 2
6.
7.
8.
9.
10.
11.
12.
13.
14.
rin in fluorescent vs. red incandescent light exposure. J Invest Dermatol 1977;69:510-2. Jaffe MZ. Ueber den Niederschlag, welcben Pikrinsaure in normalem Ham erzeugt and ueber eine neue Reaction des Kreatinins. Z Physiol Chem 1886;10:391-400. Smith SG. The use of thin layer chromatography in the separation of free porphyrins and porphyrin methyl esters. Br J Dermatol 1975;93:291-5. Lim CK, Peters TJ. High-performance liquid chromatography of uroporphyrins and coproporpliyrinisomers. Methods Enzymol 1986;123:383-9. Guo R, Lim CK, Peters JJ. Accurate and specific HPLC assay of coproporphyrinogen HI oxidase activity in human peripheral leucocytes. Clin Chim Acta 1988;177:245-52. Nunn AVW, Norris P, Hawk JLM, et al. Zinc cbelatase in human lymphocytes: detection of the enzymatic defect in erythropoietic protoporphyria. Anal Biochem 1988; 174: 146-50. Tsai S-F, Bishop DF, Desnick RJ. Coupled-enzyme and direct assays for uroporphyrinogen 111 synthase activity in human erythrocytes and cultured lymphoblasts. Anal Biochem 1987;166:120-33. Piomelli S, Poh-FitzpatrickMB, Seaman C, et al. Complete suppression of the symptoms of congenital erythropoietic porphyria by long-term treamaent with high-level transfusion. N Engl J Med 1986;314:1029-31. Tonz O, Vogt J, Filippini L, et al. Schwere Lichtdermatose nach Phototherapie bei einem Neugeborenen mit kongenitaler erythropoietischer Uroporphyrie. Helv Paediatr Acta 1975;30:47-56. Verstraeten L, Regemorter NV, Pardou A, et al. Biochemical diagnosis of a fatal case of Gunther's disease in a new-
Huang et al.
15.
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927
born with hydrops foetalis. Eur J Clin Chem Clin Biochem 1993;31:121-8. Kench JE, Langley FA, Wilkenson JF. Biochemical and pathological studies of congenital porphyria. Q J Med 1953;22:285-95. Deybach JC, deVemeuil H, Booledifar S, et al. Point mutations in the uroporphyrinogen HI synthase gene in congenital erythropoietic porphyria (Gunther's disease). Blood 1990;75:1763-5. Nordmann Y, Amaram D, Deybach JC, et al. Coexistent hereditary coproporphyria and congenital erythropoietic porphyria (Gunther' s Disease). J Inherit Metab Dis 1990; 13: 687-91. Warner CA, Yoo HW, Roberts AG, et al. Congenital erythropoietic porphyria: identification and expression of exonic mutations in the uroporphyrinogen III synthetase gene. J Clin Invest 1992;89:693-700. Xu W, Warner CA, Desnick RJ. Congenital erythropoietic porphyria: identification and expression of 10 mutations in the uropo~hyrinogen In synthase gene. J Clin Invest 1995;95:905-12. Warner CA, Poh-Fitzpatrick MB, Zaider EF, et al. Congenital erythropoietic porphyria. A mild variant with low uroporphyrin I levels due to a missense mutation (A66V) encoding residual uroporphyrinogen 11I synthase activity. Arch Dermatol 1992;128:1243-8. Bloom K, Zaider E, Morledge I_J, et al. Urinary excretion of porphyrin in normal children. Am J Kidney Dis 1991; 18:483-9.
22. Poh-Fitzpatrick MB, Zaider E, Sciales C, et al. Cutaneous photosensitivity and coproporphyrin abnormalities in the Alagille syndrome. Gastroenterology 1990;99:831-5.
and Bronx, New York Blistering of light-exposed skin, pink-stained fluorescing diapers, and fluorescing peripheral erythrocytes led to diagnosis of congenital porphyria in an infant born to consanguineous parents. Although massive coproporphyrinuria and coproporphyrinemia initially suggested a coproporphyrinogen oxidase deficiency disorder, excess porphyrins were chiefly of the isomer I series, implicating a uroporphyrinogen llI synthase defect. Congenital erythropoietic porphyria was confirmed by demonstration of a profound defect in the activity of the infant's uroporphyrinogen HI synthase (4% of the mean value for nine normal controls) and in both parents at approximately 50% of the mean normal activity. Coinheritance of gene defects for either hereditary coproporphyria or erythropoietic protoporphyria in addition to those for congenital erythropoietic porphyria was excluded by demonstrating normal activities of both coproporphyrinogen oxidase and ferrochelatase in the infant. The complicated perinatal and postnatal clinical course and biochemical and enzyme assay data for the infant and his parents are described. (J AM ACAODERMATOL1996;34:924-7.) Congenital erythropoietic porphyria (CEP), a rare autosomal recessive disorder of heme synthesis, resuits from partial deficiency of uroporphyrinogen HI synthase (URO-S, formerly termed uroporphyrinogen HI cosynthase) activity that typically leads to accumulation of porphyrins of the isomer I type.l-3 Uroporphyrin I is usually the predominant urinary and plasma metabolite, whereas coproporphyrin I predominates in feces, and increased uro-, coproand protoporphyrins may all occur in erythrocytes. CEP is clinically manifested by cutaneous photosensitivity and hemolytic anemia of varying severities and their complications. Onset occurs most often in infancy but occasionally in adult life. From the Department of Dermatology, New York Medical College, Valhalla,a the Department of Dermatology, Columbia University College of Physicians and Surgeons, New York City,t' the Division of Neonatology, Department of Pediatrics,Cand Division of Dermatology, Department of Medicine, d Montefiore Medical Center, Albert Einstein College of Medicine, Bronx. Supported by research grant ROI AR18549 from the National Institute for Arthritis, Musculoskeletal, and Skin Diseases, DHHS, Bethesda, Maryland. Reprint requests: Maureen B. Poh-Fitzpatrick, MD, Columbia/St. Luke's-Roosevelt, 432 W. 58th St., AJA 206, New York, NY 10019. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0 16/4/69109
924
We report a case of porphyria, diagnosed shortly after birth, in which the predominant urinary, fecal, plasma, and erythrocyte porphyrins were coproporphyrin I. The stormy clinical course experienced by this infant and the laboratory investigations of the child and his parents, indicating a diagnosis of CEP, are described. CASE R E P O R T
A son was born to Hispanic parents who were first cousins and had one previous child, who was healthy. There was no family history of photosensitivity or of porphyria. The infant was delivered at term; meconiumstained amniotic fluid was noted. Shortly after birth, respiratory distress, temperature instability, bloody urine and stool, and jaundice developed. Physical examination was notable for tachypnea, tachycardia, a soft systolic murmur, and hepatosplenomegaly. Pertinent laboratory abnormalities included a hematocrit value of 32.9% with 4.2% reticulocytes, 76,000 platelets per cubic millimeter, serum total bilirubin of 9.8 mg/di with a direct component of 6.8 mg/dl, and prolonged prothrombin and partial thomboplastin times. A direct Coombs' test yielded negative findings. On day 9, marked facial edema was noted; vesicles and bullae appeared on the infant's face, trunk, and extremities. A urine-soaked diaper was discolored; it fluoresced pink with Wood's light illumination. Periph-
Journal of the American Academy of Dermatology Volume 34, Number 5, Part 2
Table I.
Huang et aL
925
Total porphyrin values in urine, feces, plasma, and erythrocytes for proband and parents
Urine ~anol/mol creatinine
85,222
Feces nmol/100 g Plasma nmogL Erythrocytes nmoFL
4,492 48,195 5,874
6
10
15 2,314
-15 409
--
< - 8 2 (infants) <40 (adult females) <33 (adult males) Not established for infants <15 <890
*The upper limit for infantile urinary porphyrin excretion is estimated at the 95th percentile confidence limit of data indicating an inverse correlation between age and porphyrin excretion in children 9 months to 18 years of age. 2l Adult limits are two standard deviations above means determined by that study from our laboratory. The fecal value is from SmithKline Beecham Laboratories; normal infant reference limits are not available. Plasma and erythrocyte values were previously established in our laboratory.
eral erythrocytes were noted to fluoresce red with darkfield microscopy using blue-violet epiluminescence, leading to laboratory evaluation for a presumptive diagnosis of porphyria. Total erythrocyte and plasma porphyrin concentrations were determined as described by Piomelli,4 and PohFitzpatrick and DeI_e~, 5 respectively. A random urine sample was similarly analyzed for total porphyrin content. Urinary creatinine was measured by a method based on the Jaffe alkaline picrate reaction.6 Urinary porphyrins were fractionated by carboxyl number by thin-layer chromatography as described by Smith] Porphyrin isomer composition was determined by means of high- performance liquid chromatography as described by Lim and Peters. 8 Fecal porphyrins were quantified chromatographically by a comrnercial laboratory. Excessive excretion of porphyrins was evident in urine and feces, and both plasma and erythrocytes contained massively abnormal porphyrin content. In all specimens examined for isomer partition, the predominant porphyrin present was coproporphyrin I. In porphyrin studies of both parents, the only abnormal finding was mildly increased zinc protoporphyrin in the mother's erythrocytes, which could not be explained by either an abnormal blood lead level or iron deficiency. Neither parent excreted abnormal levels or isomer ratios of urinary porphyrins. Quantitative data are given in Tables I and II. Although large amounts of the isomer I series porphyfins suggested CEP, the stormy clinical course and overwhelming preponderance of coproporphyrins rather than uroporphyrins in all specimens led to concern that multiple gene defects encoding deficient activity in more than one of the heine biosynthetic enzymes might have been inherited, particularly those associated with hereditary coproporphyria or a variant of erythropoietic protoporphyria. Accordingly, activities of the enzymes defective in those disorders were measured in leukocytes from the patient: coproporphyrinogen oxidase as described by Guo, Lim, and Peters 9 and ferrochelatase as described by Nunn et al.m0 Activity levels for both were found to be
Table
II. Porphyrin isomer partitioning in proband's urine
I %of total Isomers
porphyrins
Ratio of I/HI
Coproporphyrin I Coproporphyrin HI Uroporphyrin I Uroporphyrin HI
75.0 3.9 11.0 0.3
19.2" 36.7
*A mean value for the ratio of coproporphyrin I/IlI previously determined in our laboratories in urine of 12 normal children ranging in age from 1.5 to 18 years is 0.4 _+ 0.222
normal. Leukocyte uroporphyrinogen HI synthase activity was measured for the infant and both parents essentially as described by Tsai, Bishop, and Desnick. ll The infant's activity was only 3.8% of a mean value estabfished for nine normal control subjects. His father and mother had 56.2% and 40.8% of the normal mean activity, respectively. These data confirmed the diagnosis of CEP. To suppress erythropoiesis and the accumulation of porphyrins, a chronic transfusion program was instituted to maintain the child's hematocrit at greater than 35%. 12 Severe hemosiderosis with extensive deposits of iron in fiver and spleen was detected by magnetic resonance imaging when the patient was 4 months old. At 6 months, deferoxmltine chelation therapy was begun in 14-day cycles at 60 mg/kg daily with a 14-day period between cycles. This resulted in reduction of serum ferritin levels from 2853 ng/ml to 1405 ng/ml over 8 months. Hepatosplenomegaly and thrombocytopenia persisted throughout the first year of life. In addition to his hematologic disease, the infant's course was complicated by anorexia, intermittent emesis, and malabsorption. At age 4 months, results of a duodenal biopsy and an upper gastrointestinal radiographic examination were normal. Although the patient initally required central total parenteral nutrition, a gastrostomy
926
Huang et al.
tube was placed for administration of a nutrient formula and cereal on which he was maintained. The patient also experienced multiple episodes of sepsis and a bemorrhagic cranial infarct during the first year of life. At 2 ~ years of age, the child is developmentally delayed. He is able to sit without assistance, is socially interactive, and is just beginning to say words. The child is kept under an amber fight-filtering film (TA-81, Madico, Saugus, Mass.) to reduce photosensitivity reactions. This practice, combined with hypertransfusion, has minimized the development of new skin lesions. He has extensive dyspigmentation and scarring of fight-exposed skin. Erythrodontia is marked in visible light. Under Wood's fight the teeth are brightly fluorescent. DISCUSSION
Congenital erythropoietic porphyria in the modem era is not uncommonly heralded by severe skin blistering that occurs after phototherapy for neonatal jaundice. 13-14 In this case, no phototherapy was given; even so, marked cutaneous photosensitivity was elicited by the ambient light of the nursery. In recent reports, cases of CEP have usually been confirmed by demonstration of uroporphyrinogen Ill synthase deficiency. Although uroporphyrin I is more often the predominant urinary metabolite in CEP, L 2 this is not the first case in which coproporphyrin I has been the greater fraction. 14-16However, the massive presence of coproporphyrin in all specimens raised the question of coexistent hereditary coproporphyria and CEP as reported by Nordmann et a1.17 In that case, the infant was also born to first cousins and presented with neonatal jaundice, hepatosplenomegaly, diffuse bleeding, thrombocytopenia, bullous skin lesions, and red urine; stunted growth and poor mental development were noted in the first year of life, as in our case. Despite the many clinical and biochemical similarities, the demonstration of normal activity of coproporphyrinogen oxidase in our case excluded that possibility. Verstraeten et al.~5 reported a case of CEP in which a severely affected infant had hydrops fetalis, hepatosplenomegaly, and anemia in utero. At birth the infant was icteric; phototherapy elicited marked photosensitivity on the first day of life. Pink urine, hypertrichosis, and fluorescing erythrocytes were noted. The infant died 24 hours after birth, exhibiting respiratory acidosis, bradycardia, and a diffuse hemorrhagic syndrome. Although enzyme assays in the infant were not done, activities of many of the heme synthetic enzymes, including those for CEP
Journal of the American Academy of Dermatology May 1996
and hereditary coproporphyria, were tested in parental specimens, revealing normal coproporphyrinogen oxidase levels but 50% reduction in normal activity for uroporphyrinogen I~ synthase for both parents. Of particular interest in reference to our case is that the infant described by Verstraeten et al. also had predominant coproporphyrin I in erythrocytes, plasma, urine, and feces. A sibling of theft patient had died in utero with similar problems. A subsequently conceived sibling of our patient was also diagnosed with CEP in utero (details to be reported separately) but died shortly after birth despite intensive care. Fourteen different mutations in the uroporphyrinogen III synthase gene have now been described in association with confirmed cases of CEP. 16' 18, 19 Some of these mutations yield greater residual activity of the encoded enzyme, conferring milder phenotypes upon their recipients, whereas other mutations encode defective enzymes with lesser activities and have been associated with more severely affected phenotypes. 1s-2° Because each of the firstcousin parents of this child are likely to be heteroallelic for the same abnormality at the locus for uroporphyrinogen HI synthase, the profoundly abnormal clinical, biochemical, and enzymatic manifestations in this case suggest that the child is homoallelic for a mutation among those linked to the most severely affected persons. The precise molecular nature of the mutant alleles encoding defective uroporphyrinogen HI synthase that are present in this family has been under study and will be separately described. We are grateful to Carolyn Raab, RN, PNP, Donna Geiss, RN, NNP, and the neonatology nursing staff of the Montefiore Medical Center for outstanding patient and family support and provision of clinical specimens; to Damaris Carriero for performing the ferrochelatase assay; and to Sergio Piomelfi, MD, for insightful scientific counsel. REFERENCES
1. KappasA, Sassa S, Galbraith RA, et al. The porphyrias. In: Stanbury JB, Wyngaarden JB, Fredickson DS, eds. The metabolic basis of inherited diseases. 6th ed. New York: McGraw-Hill, 1989;1305-65. 2. Nordmann Y, DeybachJC. Congenital erythropoieticporphyria. Sere Liver Dis 1982;2:154-63. 3. Romeo G, Levin EY. UroporphyrinogenIll cosynthase in human congenitalerythropoieticporphyria.Proc Natl Acad Sci U S A 1969;63:856-63. 4. Pi°melli S"A micr°meth°d f°r free erythr°cytep°rphyrins: the FEP test. J Lab Clin Med 1973;81:932-40. 5. Poh-FitzpatrickMB, DeLeo VA. Rates of plasma porphy-
Journal of the American Academy of Dermatology Volume 34, Number 5, Part 2
6.
7.
8.
9.
10.
11.
12.
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