Hepatoerythropoietic porphyria misdiagnosed as child abuse: cutaneous, arthritic, and hematologic manifestations in siblings with a novel UROD mutation.

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.

The very first description of a patient with hepatoerythropoietic porphyria in Argentina. Biochemical and molecular studies.

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.

Porfirias poco frecuentes: Casos detectados en la población argentina / Non frequent porphyrias in the argentinean population

Las porfirias son consecuencia de fallas en el metabolismo del hemo. Se clasifican según el tipo de sintomatología clínica prevalente o el órgano donde se expresa preferencialmente la falla metabólica. En general la deficiencia enzimática está asociada a mutaciones en los genes que codifican para cada una de las enzimas. Están descritos 7 tipos de porfiria diferentes. Se transmiten por carácter autosómico dominante a excepción de la PCE, la PHE y la NPA que son recesivas. Sin embargo, están reportadas variantes homocigotas para el resto de las porfirias de pronóstico y evolución mucho más grave que la forma heterocigota. La descripción de estos casos poco frecuentes, sus tratamientos y evolución, facilitarían tanto el diagnóstico diferencial de la porfiria como el conocimiento de las posibilidades terapéuticas en cada caso. Asimismo para las porfirias heterocigotas con manifestación infantil, su identificación temprana y tratamiento aseguraría una mejor evolución minimizando los riesgos asociados. Se han diagnosticado 5 casos de porfirias agudas en niñas: 2 de PAI, 2 de PV y 1 de CPH. Entre las porfirias cutáneas se presentan 25 casos de PCT infantil, el primer caso de PHE en Argentina, 4 casos de PCE infantil y 1 en un adulto y 2 casos de PPE con compromiso hepatobiliar.

The Porphyrias are a group of diseases resulting from partial deficiencies in one of the heme biosynthetic enzymes. These disorders can be classified on the basis of their clinical manifestations or according the organ where the metabolic deficiency is mainly expressed. In general this enzyme deficiency is associated with mutations in the genes which codify each enzyme. There are 7 types of Porphyrias. They are autosomal dominant disorders with the exception of PCE, PHE and NPA which are recessive. However, some rare and severe cases with recessive inheritance have also been reported. The description of these infrequent cases and their treatments and evolution would make easier the differential diagnosis of Porphyrias as well as the therapeutic possibilities to be applied in each case. Moreover, it is very important the early identification and treatment of infantile heterozygous porphyrias to avoid the risks of associatedd complications. In the CIPYP we have diagnosed 5 cases of infantil Acute Porphyrias: 2 PAI, 2 PV and 1 CPH. In the group of Cutaneous Porphyrias we present 25 cases of infantil PCT, the first case of PHE in Argentina, 4 cases of infantil PCE and 1 adult PCE and 2 cases of PPE with hepatic failure.

Modern diagnosis and management of the porphyrias.

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.

1599: first iconographic description of hepatoerythropoietic porphyria.

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.

Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias.

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.

Erythropoietic protoporphyria: altered phenotype after bone marrow transplantation for myelogenous leukemia in a patient heteroallelic for ferrochelatase gene mutations.

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.

New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care.

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.

Mutations in familial porphyria cutanea tarda: two novel and two previously described for hepatoerythropoietic porphyria.

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.

Myelodysplastic syndrome terminating in erythropoietic protoporphyria after 15 years of aplastic anemia.

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.

Erythropoietic protoporphyria with severe liver dysfunction and acute pancreatitis.

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.

Erythropoietic protoporphyria with antinuclear antibody positivity: avoiding misdiagnosis of systemic lupus erythematosus.

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.

Porphyrins, porphyrin metabolism and porphyrias. IV. Pathophysiology of erythyropoietic protoporphyria--diagnosis, care and monitoring of the patient.

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.