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Background: Hepatoerythropoietic porphyria (HEP) is a rare autosomal recessive disorder resulting from the markedly deficient, but not absent, activity of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD). The disorder typically manifests during infancy or early childhood with extreme photosensitivity, skin fragility in sun-exposed areas, hypertrichosis, erythrodontia, and pink urine., Observations: Three siblings, offspring of parents of Puerto Rican and Dominican descent, had with excessive scarring on the face and dorsal aspect of the forearms, which initially led to the erroneous suspicion of child abuse. Although these lesions were photodistributed, overt photosensitivity had not been observed, with the exception of a single episode of blistering and onycholysis after intense sun exposure in 1 affected child. Mild facial hypertrichosis, chronic anemia, polyarticular arthritis, and developmental delay represented additional findings. Biochemical studies of urine, plasma, and erythrocyte porphyrins from the affected siblings established the diagnosis of HEP. Sequencing of the UROD gene revealed compound heterozygosity for a novel missense mutation, V166A, and a complex deletion/insertion, 645del1053ins10., Conclusions: Our report expands the phenotypic and genotypic spectrum of HEP, highlighting mild cutaneous presentations that can occur without obvious photosensitivity and masquerade as child abuse.

Hepatoerythropoietic Porphyria (HEP) is the rare homozygous form of Porphyria Cutanea Tarda (PCT). It is characterized clinically by the early onset of severe skin manifestations which can be confused with Congenital Erythropoietic Porphyria (CEP) or with PCT when the symptoms are mild. We describe the case of a 14 year-old child with skin manifestations similar to those observed in PCT. The biochemical assays ruled out a CEP as well as they suggested the development of a HEP. Although his symptoms were not severe enough to be HEP, the enzymatic activity was dramatically reduced to a 5% of normal values and the molecular analysis revealed the presence of two already known different mutations on the patient's URO-D gene, c.703 C>T and IVS9-1. Each parent carry one of the mutations, but they were absent in the brother. This is the first Argentinean HEP case ever described which appeared in a compound heterozygous form and less residual URO-D activity but associated to a mild phenotype.

Recent advances in the molecular understanding of the porphyrias now offer specific diagnosis and precise definition of the types of genetic mutations involved in the disease. Molecular diagnostic testing is powerful and very useful in kindred evaluation and genetic counselling when a disease-responsible mutation has been identified in the family. It is also the only way to properly screen asymptomatic gene carriers, facilitating correct treatment and appropriate genetic counselling of family members at risk. However, it should be noted that DNA-based testing is for the diagnosis of the gene carrier status, but not for the diagnosis of clinical syndrome or severity of the disease, e.g. an acute attack. For the diagnosis of clinically expressed porphyrias, a logical stepwise approach including the analysis of porphyrins and their precursors should not be underestimated, as it is still very useful, and is often the best from the cost-effective point of view.

The author's aim was to contribute information to the history of porphyrias through the analysis of a 16th century portrait. The subject drawn by physician Aldrovandi is a 20-year-old girl showing remarkable facial hypertrichosis, while her body is described as hairless. After a brief excursus through the history of porphyrias, the author revisited a previous diagnosis of hypertrichosis lanuginosa with the aid of current clinical findings. Accurate research of the drawings by the 16th century physician together with the study of our case's family history have supplied information on the young woman affected by hirsutism, such as the absence of hair on her body surface. Careful observation together with updated knowledge resulted in a diagnosis of hepatoerythropoietic porphyria; a disease characterized by severe facial hypertrichosis, a hairless body, and very early onset and heredity.

We have recently demonstrated that in an autosomal dominant porphyria, erythropoietic protoporphyria (EPP), the coinheritance of a ferrochelatase (FECH) gene defect and of a wild-type low-expressed FECH allele is generally involved in the clinical expression of EPP. This mechanism may provide a model for phenotype modulation by minor variations in the expression of the wild-type allele in the other three autosomal dominant porphyrias that exhibit incomplete penetrance: acute intermittent porphyria (AIP), variegata porphyria (VP) and hereditary coproporphyria (HC), which are caused by partial deficiencies of hydroxy-methyl bilane synthase (HMBS), protoporphyrinogen oxidase (PPOX) and coproporphyrinogen oxidase (CPO), respectively. Given the dominant mode of inheritance of EPP, VP, AIP and HC, we first confirmed that the 200 overtly porphyric subjects (55 EPP, 58 AIP, 56 VP; 31 HC) presented a single mutation restricted to one allele (20 novel mutations and 162 known mutations). We then analysed the available single-nucleotide polymorphisms (SNPs) present at high frequencies in the general population and spreading throughout the FECH, HMBS, PPOX and the CPO genes in four case-control association studies. Finally, we explored the functional consequences of polymorphisms on the abundance of wild-type RNA, and used relative allelic mRNA determinations to find out whether low-expressed HMBS, PPOX and the CPO alleles occur in the general population. We confirm that the wild-type low-expressed allele phenomenon is usually operative in the mechanism of variable penetrance in EPP, but conclude that this is not the case in AIP and VP. For HC, the CPO mRNA determinations strongly suggest that normal CPO alleles with low-expression are present, but whether this low-expression of the wild-type allele could modulate the penetrance of a CPO gene defect in HC families remains to be ascertained.

Acute myelogenous leukemia occurred in a 47-year-old woman whose 25-year history of cutaneous photosensitivity had been undiagnosed until abnormally high erythrocyte, plasma, and fecal protoporphyrin levels were discovered during evaluation for her hematologic disorder. She was found to be heteroallelic for ferrochelatase gene mutations, bearing a novel missense mutation caused by a C185-->G (Pro62-->Arg) transversion in exon 2 of one allele, and a previously described g-->a transition at the +5 position of the exon 1 donor site of the other allele, confirming a diagnosis of erythropoietic protoporphyria. Successful bone marrow transplantation from her brother, who is a mildly affected bearer of the second mutation, resulted in remission of the leukemia and in conversion of the protoporphyria phenotype of the recipient to one resembling that of the donor.

A case of liver transplantation is described in a 35-year-old male with hepatic failure due to erythropoietic protoporphyria. Data regarding protoporphyrin levels in erythrocytes and faeces, before and after transplantation, seem to indicate that, in this case, protoporphyrin overproduction was, in part, due to liver synthesis. Four years after surgery, the patient is completely free of skin photosensitivity. Liver function tests are normal and there are no significant protoporphyrin deposits in the new liver. However, recurrence of the disease in the long-term cannot be excluded, since erythrocyte protoporphyrin levels have remained elevated after liver transplantation.

In a five-year-old girl with photosensitivity (burning skin sensation after a sun bath) and purpura on the nose and the sides of the fingers erythropoietic protoporphyria was diagnosed, an autosomal dominant disease.

An extremely painful cutaneous condition with no or only slight visible skin changes, presenting in a child or an adult as an acute reaction to sun light, is probably a manifestation of the porphyrin metabolic disorder erythropoietic protoporphyria (EPP). The disease is the result of a genetically determined condition where a mutation in the gene for the final enzyme in the haem synthetic chain, ferrochelatase, results in impaired activity of the enzyme. In some predisposed individuals, the condition is accompanied by heavy accumulation of the substrate for the deficient enzyme, i.e. of protoporphyrin. Distributing to the skin, and there absorbing light of certain wavelengths, the metabolite generates free radicals that give rise to photodynamic cell injury. The primary event takes place in the endothelial cells of the superficial skin capillaries, but complement activation and mast cell degranulation in the surrounding tissue follow in the process. Even if the disease is primarily dermatological the hepatic and psychosocial complications are features requiring close attention by the physician. In order to provide a basis for suggestions regarding lege artis protocols for the diagnosis, treatment and monitoring of the patient with EPP, the pathophysiology of the cutaneous and hepatic manifestations are discussed in some detail in the article.

Unlabelled: Erythropoietic protoporphyria (EPP, MIM 177000) is an inherited disorder caused by a partial deficiency of ferrochelatase (FECH) which catalyses the chelation of iron into protoporphyrin to form haem. The majority of EPP patients experience solely a painful photosensitivity whereas a small number of them develop liver complications due to the accumulation of excessive amount of protoporphyrin in the liver. EPP is considered to be an autosomal dominant disorder, however, with a low clinical penetrance. To date, a total of 65 different mutations have been identified in the FECH gene of EPP patients. Among the 89 EPP patients who carry a "null allele" mutation which results in the formation of a truncated protein, 18 of them developed EPP-related liver complications. None of the 16 missense mutations identified among 19 patients on the other hand, have been associated with liver disease (P = 0.038). The allelic constellation of an overt patient consists of a mutated FECH allele and a "low expressed" normal allele and that of an asymptomatic carrier, a combination of a mutated and a normally expressed FECH allele. The identification of the "low expressed" allele is facilitated by haplotype analysis using two single nucleotide polymorphisms, -251 A/G in the promoter region and IVS1-23C/T. At the current time when only partially effective therapies are available, the disclosures of both "null allele" and the "low expression" mechanisms will improve patient management., Conclusion: While covering the important clinical aspect of erythropoietic protoporphyria, this article emphasises the latest achievements in the molecular genetics of the disorder.

Uroporphyrinogen decarboxylase (URO-D) deficiency is responsible for two forms of genetic cutaneous porphyria: familial porphyria cutanea tarda (f-PCT) and hepatoerythropoietic porphyria (HEP). The f-PCT transmitted as an autosomal dominant trait, is characterized by photosensitive cutaneous lesions frequently associated to hepatic dysfunction and is precipitated by various ecogenic factors. The HEP, transmitted as a recessive trait, is more severe than f-PCT and would be considered as the homozygous form of f-PCT. For the mutational analysis of f-PCT patients, the entire URO-D gene was amplified and each exon, intron-exon boundaries and the promoter region were cycle sequenced. Five mutations were found in 6 unrelated families studied, of these, two were new: a nonsense mutation in exon 6 (W159X) and a splice defect in intron 9 (IVS9(-1)G-->C). The other two missense mutations, P62L and A80G, had been previously reported in the homozygous state in HEP families. The g10insA, reported in our laboratory, was again identified in other two unrelated families. In addition 3 novel URO-D polymorphisms in non-coding regions were found. The reverse transcription-PCR and sequencing of the splice mutation carrier's RNA did not reveal the presence of an abnormal mRNA, suggesting that no stable transcript from the mutated allele is synthesized. These results increase to 39 the number of mutations identified in the URO-D gene; 4 of them causing both HEP and f-PCT., (Copyright 2000 Wiley-Liss, Inc.)

The authors report a case of aplastic anemia in which refractory anemia, a subtype of myelodysplastic syndrome (MDS), developed 15 years after the onset and was subsequently followed by erythropoietic protoporphyria (EPP). Defects of stem cells in MDS are thought to be responsible for the disturbance of the heme biosynthetic pathway, leading to the development of EPP.

A case of erythropoietic protoporphyria associated with severe hepatic dysfunction and acute pancreatitis is reported. The patient, a 33-year-old man, was admitted to our hospital complaining of upper abdominal pain, nausea, and vomiting of 3 days' duration. Laboratory tests on admission demonstrated liver dysfunction, anemia, and thrombocytopenia. On the third hospital day, the intensity of the upper abdominal pain increased, concomitantly with elevated levels of serum amylase. Ultrasonography and computed tomography scanning revealed a slightly enlarged pancreas. During this episode, he also complained of various neurological symptoms, including reduced mental alertness, weakness of extremities, constipation, profound sweating, and urinary retention. Porphyrin studies demonstrated markedly elevated erythrocyte and fecal protoporphyrin levels. Laparoscopic findings obtained after the attack subsided were compatible with porphyric liver cirrhosis. We therefore concluded that neurologic disorders and acute pancreatitis could develop in patients with erythropoietic protoporphyria with severe liver dysfunction.

A young eunuchoid man was referred to our hospital with suspected erythropoietic protoporphyria. Serum antinuclear antibody (ANA) was found to be positive immediately after the porphyria attack and disappeared 30 days later. Many authors have mentioned the coexistence of systemic lupus erythematosus (SLE) and porphyria. As these two disorders have similar clinical features, the clinician must be alert and use strict diagnostic criteria in determining the presence of SLE with porphyria. In the past, elevation of ANA was reported in the cases of acute intermittent porphyria. However, there have been no reports in the cases of erythropoietic protoporphyria. In addition, the patient was found to have hypogonadotropic hypogonadism consistent with Kallmann's syndrome. To our knowledge, this report is the first case showing the coexistence of Kallmann's syndrome and erythropoietic protoporphyria. As yet, the clinical importance of this association remains unknown.

Severe liver failure is a rare complication of erythropoietic protoporphyria (PEP), which is associated with a high rate mortality. Until now, 31 patients with this hepatic complication had underwent a liver transplantation, with a high rate of survival, but their long-term outcome is not well established. We report the first case in Spain of PEP in 59-year-old, whose acute liver failure was treated with liver transplantation, without postoperative complications. The patient is in good clinical condition 30 months later. Nevertheless during the first eleven months of follow-up the plasma levels of protoporphyrin remained elevated, which was accompanied of biochemical and histological evidence of relapse of the metabolic disease in the graft. Cases such as this stress the usefulness of liver transplantation, but also the need of more efficient measures to decrease the protoporphyrin levels before and after the transplant, in order to prevent hepatic and extrahepatic complications in these patients.

Background: Erythropoietic protoporphyria (EPP) results from an inherited deficiency of the last enzyme of the heme biosynthetic pathway, ferrochelatase (FC). EPP is usually inherited in an autosomal dominant fashion, and the mutations in the FC gene on chromosome 18q21.3 detected in EPP patients are heterogeneous., Methods: In this study, we screened the FC gene for mutations in 12 patients from 10 unrelated families with EPP and their family members using heteroduplex analysis, automated sequencing, and restriction enzyme digestion., Results: We detected 8 different mutations in these patients, including 1 missense mutation, 5 frameshift mutations, and 2 splice site mutations, 6 of which are previously undescribed., Conclusions: We have established the molecular basis of EPP in 10 unrelated families, thereby providing further evidence for the heterogeneity in this disorder. Importantly, molecular diagnosis allowed revisions in the status of several clinically unaffected silent mutation carriers within the families. We compare the value of genetic research strategies with the combination of biochemical data and clinical phenotype as diagnostic tools to confirm a putative diagnosis in EPP.

Many patients with cutaneous porphyria have curable or controllable disease; untreated porphyria may prove fatal. The genetic defects and mechanisms underlying porphyria are steadily being delineated, treatments have become more appropriate and genetic counselling is now more accurate. A summary of the basic diagnostic features, management and recent advances in the cutaneous porphyrias is presented, based on a workshop held by the British Photodermatology Group.

We report the case of a 4-year-old girl, who had been suffering for 2 years from a recurrent, painful crisis affecting both hands, following sun exposure. There were no obvious cutaneous lesions, which initially caused us to consider a diagnosis of a psychiatric disorder. However, the diagnosis of erythropoietic protoporphyria was then established by the demonstration of elevated levels of free protoporphyrin in erythrocytes. The present case illustrates the effectiveness of beta-carotene associated with canthaxanthin in erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is an autosomal dominant inherited disorder with incomplete penetrance. It is caused by partial deficiency of ferrochelatase, the last enzyme in the heme biosynthetic pathway. Measurement of protoporphyrin concentrations in red cells and feces, although sufficient for diagnosis of symptomatic EPP patients, fails to detect asymptomatic gene carriers. We have developed a molecular diagnostic procedure for rapid and reliable screening of five known mutations in the ferrochelatase gene among Swiss EPP patients in a single denaturing gradient gel electrophoresis (DGGE) gel.

Erythropoietic protoporphyria (EPP) presents clinically as a painful skin reaction to sun-light exposure. The profoundly disabling psychosocial consequences of the disease often go unnoticed by the physician, and the need to monitor the patient for hepatic complications is not generally recognised. The article describes the clinical and biochemical course in a 51-year-old man with EPP, who within a few days developed signs of acute hepatic failure. The case emphasises the importance of a well designed monitoring programme that allows close evaluation of the patient's current porphyrin metabolism, and indicates what measures should be considered.

Human protoporphyria results from mutations in the ferrochelatase gene. Heritable deficiency of ferrochelatase causes overproduction of protoporphyrin IX, principally in the erythron. Photosensitivity is a universal feature of protoporphyria but hepatic clearance of the hydrophobic protoporphyrin molecule with excretion in bile may lead to precipitation within biliary pathways. Thus cholestatic injury and protoporphyrin gallstones occur. Minor hepatic abnormalities are frequent, but at least 30 patients have been reported with a progressive liver disease that requires transplantation. Fulminant hepatic disease appears to be recessively inherited in some pedigrees. Hazards of liver transplantation include tissue photolysis, hemolysis, and an unexplained neurological syndrome, but most of the 15 patients reported after transplantation have survived for several months to > 6 years. Aspects of protoporphyria, its pathogenesis and contemporary therapeutic strategies are considered, with emphasis on hepatic sequelae.

CT and MR findings in two patients with hepatoerythropoietic porphyria are presented. CT scans showed atrophy and cortical mineralization at the same level. MR examination performed in one of the two patients showed mainly frontal cortical atrophy and punctate bright signal on T1- and T2-weighted sequences.

Hepatoerythropoietic porphyria is characterized by an early beginning of severe photosensitivity, with an increase in urinary uroporphyrin excretion and other porphyrins, high isocoproporphyrin fecal levels and an accumulation of protoporphyrin in erythrocytes. It is caused by a dramatic decrease in the activity of the uroporphyrinogen decarboxylase. We report a clinical, biochemical and enzymatic study in a family, where a 2-year-old girl suffers from a hepatoerythropoietic porphyria, and the patient's maternal uncle from a porphyria cutanea tarda. We discuss the relationship between these diseases and their known mutations.

The porphyrias are uncommon diseases caused by enzymatic deficiencies in the heme pathway. In the 25 year period 1969-1994, the Department of Dermatology of the Hospital Clinic of Barcelona has been able to study 793 cases of porphyria (724 cases of PCT, 27 of EPP, 26 of PV, 5 of CEP, 5 of HEP, 5 of AIP, 1 of HCP). Homozygous expression of an enzymatic deficiency in the heme pathway produces severe disease. Commonly, clinical manifestations appear in the homozygous state (the autosomal recessive porphyrias). However, homozygous forms of autosomal dominant porphyrias may occur exceptionally. Moreover, there are cutaneous porphyrias whose clinical manifestations do not permit dermatologists to classify them clearly into one of the well-defined syndromes. These uncommon and atypical forms are difficult to recognize without biochemical and enzyme studies. The porphyrias have a wide clinico-biochemical spectrum, including a large proportion of well defined diseases. Nevertheless, atypical forms occur and may be difficult to evaluate. It is important to note the genetic heterogeneicity of porphyrias, which accounts for the varying phenotypic expression.

Variegate porphyria (VP) is a dominantly inherited acute hepatic porphyria characterized by a 50% decrease in activity of protoporphyrinogen oxidase (PO) which catalyses the last step of heme biosynthesis. In VP families, most of the gene carriers are asymptomatic but at risk of developing acute attacks if subjected to precipitating factors. Recognition of the carrier status is the first step of an efficient preventive care. This could be achieved by measurement of PO activity which is a sensitive and specific but tedious method. A specific plasma fluorometric emission at 626 nm has been shown in VP patients. Here we show that this simple and inexpensive method is specific but poorly sensitive, especially in detection of asymptomatic carriers. We conclude that this procedure should not replace PO activity measurement in VP family studies.

Porphyria cutanea tarda (PCT) is induced by an enzyme deficiency of hepatic uroporphyrinogen decarboxylase activity. As the result of this enzyme deficiency, uroporphyrin and coproporphyrin accumulate to the skin and other organs. These porphyrins are excreted into urine because of their easy solubility in water. Exposure to the sunlight of the porphyrin-rich skin induces cutaneous changes. Porphyria cutanea tarda develops mainly in middle-aged males, sometimes in females. Ethylalcohol, estrogenic hormones, and hemodialysis are reported as provocative factors. Hyperpigmentation on exposed areas, skin fragility, vesicles and erosions are common in PCT. Histopathologically, subepidermal bulla is a characteristic finding in PCT. PAS positive materials are also prominent around the small blood vessels in the dermis and dermo-epidermal junctions. Hepatoerythropoietic porphyria (HEP) is usually manifest in early childhood with dark urine and reveals severe cutaneous photosensitivity. This disease is a homozygous form of type II PCT.

Erythropoietic protoporphyria is an autosomal inherited disease characterized by decreased ferrochelatase activity. This abnormality results in excess protoporphyrin accumulation not only in red blood cells but also in other organs such as skin, and causes various degrees of skin photosensitivity according to degrees of decreased ferrochelatase activity. An excess protoporphyrin accumulation in liver results in severe liver damage which might cause juvenile death in some patients. Clinical views including its diagnosis and treatment are briefly summarized, and possible relationship between skin porphyrin level and skin photosensitivity is discussed.

Porphyria in childhood is an uncommon problem but the recognition of these disorders is vitally important for affected children. Of the cutaneous porphyrias, erythropoietic protoporphyria, congenital erythropoietic porphyria, hepatoerythropoietic porphyria, and the hereditary form of porphyria cutanea tarda (PCT) can present in infancy or childhood. This article focuses on the porphyrias that present in infants and children along with a brief discussion of pathogenesis, cutaneous histopathology, and genetics of these metabolic disorders.

Erythropoietic protoporphyria is an autosomal dominant hereditary disorder with irregular penetrance. Recently, the first molecular DNA defects have been published. Various courses the disease may take are illustrated by three cases. The main symptom is photosensitivity, usually beginning in early childhood. Development of gallstones at an early age is one possible complication. Terminal liver failure, a rare but fatal complication, is due to intrahepatic protoporphyrin deposition and is treatable by liver transplantation only. Possible treatment schemes for photosensitivity and for liver involvement are discussed.