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Familial Porphyria Cutanea Tarda

Synonyms: Familial PCT; F-PCT; Porphyria Cutanea Tarda, Type II; Type II PCT

, MD, , PhD, , MD; .

Author Information

Initial Posting: ; Last Update: September 8, 2016.

Estimated reading time: 19 minutes

Summary

Clinical characteristics.

Familial porphyria cutanea tarda (F-PCT) is characterized by: skin findings including blistering over the dorsal aspects of the hands and other sun-exposed areas of skin, skin friability after minor trauma, facial hypertrichosis and hyperpigmentation, and severe thickening of affected skin areas (pseudoscleroderma); and an increased risk for hepatocellular carcinoma (HCC).

Diagnosis/testing.

The diagnosis of F-PCT is established in a proband by identification of elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin) and confirmed by the identification of a heterozygous UROD pathogenic variant.

Management.

Treatment of manifestations: Reduction of body iron stores and liver iron content preferably by phlebotomy;low-dose antimalarial agents (chloroquine or hydroxychloroquine); eliminate known susceptibility factors including excess hepatic iron, alcohol consumption, smoking, oral estrogens, and hepatotoxins. In persons with end-stage renal disease, erythropoietin therapy has been shown to correct anemia, mobilize iron, and support phlebotomy. Iron chelation therapy (e.g., deferasirox, deferiprone, or desferrioxamine) may be considered if phlebotomy is contraindicated.

Prevention of primary manifestations: Identification and avoidance of susceptibility factors (where applicable); protection from sunlight in the symptomatic phase; vaccination against hepatitis A and B.

Surveillance: Monitor urinary porphyrin levels annuall; resume phlebotomies when levels begin to rise. Monitor annually for diabetes mellitus with fasting glucose. Monitor for HCC annually with serum AFP concentration and hepatic ultrasonography; monitor every six months in those with advanced chronic hepatitis C and/or alcoholic cirrhosis.

Agents/circumstances to avoid: Susceptibility factors (e.g., iron supplements, alcohol consumption, smoking, oral estrogen, and hepatotoxins); exposure to sunlight in symptomatic phase.

Evaluation of relatives at risk: If the family-specific UROD pathogenic variant is known, clarify the genetic status of at-risk relatives so that those with a UROD pathogenic variant can avoid known susceptibility factors.

Genetic counseling.

F-PCT is inherited in an autosomal dominant manner. At least one parent of most individuals with F-PCT has a UROD pathogenic variant; however, few individuals diagnosed with F-PCT have a clinically affected parent because penetrance is significantly reduced. Each child of an individual with F-PCT has a 50% chance of inheriting the pathogenic variant. Because of reduced penetrance, the likelihood of the offspring developing clinical manifestations of F-PCT is small. Prenatal diagnosis for a pregnancy at increased risk is possible if the pathogenic variant in an affected family member is known. Because of reduced penetrance, results of prenatal testing are not useful in accurately predicting whether or not an individual with one UROD pathogenic variant will develop F-PCT or if so, the age of onset or specific symptoms.

Diagnosis

Suggestive Findings

Familial porphyria cutanea tarda (F-PCT) should be suspected in individuals with the following clinical and biochemical features.

Clinical features (typically developing in the 4th-5th decade):

  • Photosensitivity resulting in fluid-filled vesicles developing over the dorsal aspects of the hands and other sun-exposed areas of skin (e.g., forearms, face and scalp, ears, neck, legs, and feet)
  • Skin fragility after minor trauma (which may occur over the same areas where the blisters develop)
  • Facial hypertrichosis and hyperpigmentation
  • Severe thickening of the affected skin areas (pseudoscleroderma) that resembles systemic scleroderma

Biochemical features (see Table 1):

  • Hepatic uroporphyrinogen decarboxylase enzyme activity is less than approximately 20% of normal. The amount of protein remains at approximately 50%.
  • Plasma porphyrins are incresed.
    Note: Levels are higher in persons with F-PCT with renal failure.
  • Urine porphyrins are elevated. Predominance of uroporphyrin and heptacarboxylporphyrin; hexa- and pentacarboxylporphyrins and coproporphyrin levels are also increased.
    Note: Isomer analysis of the uroporphyrin shows a significant increase in isomer I uroporphyrin.
  • Stool heptacarboxylporphyrin, isocoproporphyrin, and pentaporphyrins are increased.
  • Urine delta-aminolevulinic acid (ALA) is normal or minimally increased.
  • Porphobilinogen (PBG) levels are normal.
  • In persons with severe F-PCT, urine may appear pink in color and fluoresces bright pink when excited by long UV-blue light.

Table 1.

Biochemical Features of Familial Porphyria Cutanea Tarda

Biochemical Finding
Deficient enzymeHepatic uroporphyrinogen decarboxylase
Enzyme activity< ~20% of normal
Plasma↑ Uroporphyrin, heptacarboxylporphyrin (~620 nm) 1
Urine↑ Uroporphyrin, heptacarboxylporphyrin
Stool↑ Heptacarboxylporphyrin, isocoproporphyrins + pentaporphyrins
1.

Fluorescence emission peak of diluted plasma at neutral pH, following excitation at 400-410 nm

Establishing the Diagnosis

The diagnosis of F-PCT is established in a proband with elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin, and identification of a heterozygous pathogenic variant in UROD by molecular genetic testing (see Table 2).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of UROD is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes UROD and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes UROD) fails to confirm a diagnosis in an individual with features of F-PCT. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in Familial Porphyria Cutanea Tarda

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
URODSequence analysis 316% 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Most individuals with familial porphyria cutanea tarda (F-PCT) develop skin changes in the fourth or fifth decade of life. Disease manifestations are more common in men than women.

Skin findings include photosensitivity resulting in the formation of blisters over the dorsal aspects of the hands and other sun-exposed areas of skin (e.g., forearms, face and scalp, ears, neck, legs, and feet), skin friability after minor trauma which can occur over the same areas where the blisters develop, facial hypertrichosis and hyperpigmentation, and severe thickening of the affected skin areas (pseudoscleroderma) that resembles systemic scleroderma.

Histopathology of the blisters in F-PCT demonstrates subepidermal blistering; deposition of PAS-positive material around blood vessels and fine fibrillar material in the upper dermis and at the dermoepithelial junction; and splits in the lamina lucida of the basement membrane [Dabski & Beutner 1991]. These findings are not diagnostic of F-PCT and can be found in other cutaneous porphyrias and pseudoporphyria.

Hepatocellular carcinoma. The risk for hepatocellular carcinoma is increased in individuals with F-PCT, especially in those with other risk factors predisposing to advanced liver disease (e.g., hepatitis C, alcoholic liver disease) [Gisbert et al 2004, Rossmann-Ringdahl & Olsson 2005, Cassiman et al 2008].

Susceptibility Factors

Several inherited, environmental, and infectious factors are known or suspected to play an important role in the development of manifestations of F-PCT; heterozygosity for a UROD pathogenic variant alone does not account for the clinical manifestations of F-PCT.

  • HFE pathogenic variants that lead to increased intestinal iron absorption increase the risk of developing F-PCT.
  • Iron overload. Mild to moderate iron overload is common in individuals with F-PCT. Some degree of hepatic siderosis is seen in almost all affected individuals. Conversely, iron deficiency has been found to be protective.
  • Alcohol. PCT has long been associated with excessive alcohol use.
  • Smoking and cytochrome P450 enzymes. Smoking is commonly associated with alcohol use in PCT [Egger et al 2002].
  • Estrogens. Estrogen use is common in women with PCT [Grossman et al 1979, Sixel-Dietrich & Doss 1985, Egger et al 2002].
  • Estrogen mimetics/antagonists (e.g., tamoxifen)
  • Toxins. PCT has been described in those exposed to hexachlorobenzene, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), chemicals that were subsequently shown to cause hepatic UROD deficiency and biochemical features resembling PCT in laboratory animals. The compounds are potent inducers of the cytochrome P450 enzymes, including hepatic CYP1A2.
  • Antioxidants. Substantial reductions in plasma levels of ascorbate and carotenoids have been noted in some individuals with PCT [Sinclair et al 1997, Rocchi et al 1999].
  • End-stage renal disease (ESRD) can lead to the development of F-PCT for reasons still not fully understood. The manifestations of F-PCT in persons with ESRD are usually more severe and sometimes include severe cutaneous mutilation. Lack of urinary porphyrin excretion in these individuals leads to much higher concentrations of porphyrins in plasma; these excess porphyrins are poorly dialyzable [Anderson et al 1990].
  • Hepatitis C. Reported prevalence of hepatitis C in individuals with PCT has ranged from 21% to 92% in various countries [Ryan Caballes et al 2012]; it is seen more frequently in type I PCT (sporadic) than in F-PCT [Muñoz-Santos et al 2010].
  • Human immunodeficiency virus (HIV). PCT is associated with HIV infection, although less commonly than with hepatitis C infection [Wissel et al 1987].

Pathophysiology

Hepatic UROD deficiency develops in the presence of multiple susceptibility factors that are believed to contribute to the generation of a UROD enzyme inhibitor. When hepatic UROD is significantly inhibited, oxidized porphyrins (mostly uroporphyrin and heptacarboxylporphyrin) accumulate in the liver and are then transported out of hepatocytes into the plasma and eventually into the urine. These excess porphyrins are deposited in the skin and other tissues.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known for F-PCT.

Nomenclature

The term, type III PCT, has been used to refer to familial PCT (i.e., >1 affected family member) not associated with mutation of UROD. There are very few well-documented reports; some of the data on the so-called type III PCT result from studies in which UROD activity has been used to diagnose individuals with type III when they in fact have F-PCT.

Penetrance

The penetrance of F-PCT is low. Usually individuals with F-PCT are simplex cases (i.e., a single occurrence in a family). No population-based studies have been done to determine the frequency of pathogenic variants in UROD in asymptomatic individuals to provide an estimate of penetrance.

Cantatore-Francis et al [2010] described a family in which three affected members (proband and 2 sibs) had compound heterozygous UROD pathogenic variants and four unaffected members (father, mother, and 2 sibs) had a heterozygous UROD pathogenic variant. The multiple and varied clinical findings of the proband age seven years and the affected sibs ages 11 years and ten years are described in detail [Cantatore-Francis et al 2010].

Prevalence

PCT is the most common type of porphyria. The proportion of F-PCT ranges from 15% to 50% of all PCT, depending on the frequency of the susceptibility factors and founder effects [Aarsand et al 2009].

Its prevalence has been estimated to range from 5:100,000 to 10:100,000, with a higher prevalence reported in certain European populations [Christiansen et al 2005, Poblete-Gutiérrez et al 2004, Badenas et al 2009].

Differential Diagnosis

Type I PCT (sporadic; no UROD pathogenic variant). Sporadic porphyria cutanea tarda (PCT) is highly influenced by susceptibility factors associated with PCT; often several are present in affected individuals, including mutation of HFE. Sporadic PCT is clinically indistinguishable from familial PCT.

African iron overload (OMIM 601195) results from a predisposition to iron overload that is exacerbated by excessive intake of dietary iron. It is particularly prevalent among Africans who drink a traditional beer brewed in non-galvanized steel drums. Mutation of other yet-to-be-defined iron-related genes predisposes to this condition. A specific pathogenic variant (p.Gln248His) in SLC40A1 (NM_014585.5) encoding ferroportin has been associated with a tendency to iron overload in Africans and African Americans [McNamara et al 2005, Rivers et al 2007]. Another probable pathogenic variant (p.Asp270Val) in SLC40A1 was discovered in an African American man with mild iron overload [Lee et al 2012].

Variegate porphyria (VP) and hereditary coproporphyria (HCP). Blistering skin lesions in VP and HCP are nearly identical to those in PCT, with the lesions being more common in VP than in HCP. In contrast, HCP is generally accompanied by neurovisceral features, especially bouts of severe abdominal pain, which are not observed in PCT.

Congenital erythropoietic porphyria (CEP) and hepatoerythropoietic porphyria (HEP). Although the skin lesions of CEP and HEP resemble those of PCT, they are usually more severe and mutilating. Also in CEP and HEP the skin lesions appear early in life (e.g., infancy and childhood), whereas in PCT the lesions generally appear during the fourth and fifth decades of life.

In both CEP and HEP the increased severity is attributed to the plasma concentration of porphyrin. Mehrany et al [2004] described a child age four years with PCT who was homozygous for the HFE p.Cys282Tyr pathogenic variant.

CEP can be mistaken for HEP or PCT; however, urine porphyrin analysis (demonstrating uroporphyrin and coproporphyrin type I) rules out these other types of cutaneous porphyria. Fecal analysis may be necessary in individuals with later onset.

Pseudoporphyria. Although the skin histopathologic findings of pseudoporphyria are indistinguishable from those of PCT, pseudoporphyria does not cause porphyrin biochemical abnormalities. Drugs are implicated in the appearance of this condition [Barzilay et al 2001].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with familial porphyria cutanea tarda (F-PCT), the following evaluations and/or testing for all known susceptibility factors are recommended:

  • Medical history regarding alcohol consumption, tobacco exposure, medication use (estrogens), exposure to hepatotoxins (e.g., hexachlorobenzene)
  • Evaluation for excess hepatic iron
  • Targeted analysis for HFE pathogenic variants (see HFE-related familial hemochromatosis)
  • Evaluation for hepatitis C and/or human immunodeficiency virus infection
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment is highly effective; it should only be initiated after the diagnosis is well established. The mainstays of therapy for PCT are reduction of body iron stores and liver iron content and use of low-dose antimalarial agents (chloroquine or hydroxychloroquine).

Iron reduction. In most centers serial phlebotomy is the preferred mode of reducing body iron stores and liver iron content. Iron chelation therapy (e.g., deferasirox, deferiprone, or desferrioxamine) is less efficient and more costly than therapeutic phlebotomies in reducing iron, but may be considered if the latter is contraindicated [Rocchi et al 1987].

Serum ferritin concentration should be measured before starting phlebotomy treatment. Typically, approximately 450 mL of blood is removed during a therapeutic phlebotomy, usually initially at two-week intervals. Hemoglobin levels (which are generally >10-11 g/dL) are followed as safety (not therapeutic) targets to prevent symptomatic anemia. The therapeutic target is to reduce the serum ferritin concentration to the low-normal range (15-25 ng/mL), which is associated with tissue iron depletion but usually not anemia.

Phlebotomy treatment is also guided by plasma (or serum) porphyrin levels, which are more convenient to measure repeatedly than urine porphyrins, and which decrease more slowly than the serum ferritin concentration. Plasma porphyrin levels usually decline from initial concentrations of 10-25 μg/dL to below the upper limit of normal (~1 μg/dL) within weeks after phlebotomies are completed [Rocchi et al 1986, Ratnaike et al 1988].

Development of new skin lesions generally ceases as plasma porphyrin levels become normal; however, therapy should be continued until the serum ferritin concentration has reached the low end of normal. The chronic skin lesions of PCT are slow to resolve, and some chronic scarring may remain indefinitely.

After a remission has been achieved, continued phlebotomies are generally not needed unless initial evaluation has determined the presence of HFE-related familial hemochromatosis. For persons with the HFE genotypes p.Cys282Tyr / p.Cys282Tyr or p.Cys282Tyr / p.His63Asp, management guidelines for HFE-related familial hemochromatosis should be followed.

Although not essential, adherence to a low-iron diet, especially with restriction of intake of red meat and liver (rich sources of heme iron, which is absorbed better than iron from vegetable sources) is reasonable, especially in those with HFE pathogenic variants. In addition, the ingestion of tea with lunch or dinner further reduces the gastrointestinal absorption of iron.

Note: Treatment of PCT in persons with end-stage renal disease is more difficult since the option for phlebotomy is often limited by anemia. However, in several instances erythropoietin therapy has been shown to correct anemia, mobilize iron, and support phlebotomy [Shieh et al 2000]. Such individuals may also be considered for iron chelation therapy.

Low-dose antimalarial agents. A low-dose regimen of twice-weekly hydroxychloroquine (100 mg) or chloroquine (125 mg) is also effective and most appropriate when phlebotomy is contraindicated or poorly tolerated [Bruce & Ahmed 1998]. Note: Chloroquine is not recommended in persons with increased serum ferritin concentration [Stölzel et al 2003].

Although the use of low-dose antimalarial agents is preferred at many centers because they are less costly and more convenient, these agents do not deplete hepatic iron and the mechanism of their action in the treatment of PCT is not fully understood. Combining both treatment modalities (i.e., antimalarial agent therapy and phlebotomy) may be beneficial if the individual is unable to tolerate full courses of phlebotomy.

Other. Individuals are advised to stop drinking alcohol and smoking and to discontinue further oral estrogen use.

Adequate intake of ascorbic acid and other nutrients may be recommended although this is not considered to be primary therapy.

PCT may also improve after treatment of coexisting hepatitis C. PCT should be treated first in most individuals:

  • PCT generally causes more symptoms and can be treated more quickly and effectively than hepatitis C.
  • Some evidence shows that hepatitis C treatment may be more effective after iron reduction [Desai et al 2012, Ryan Caballes et al 2012].
  • Both interferon and ribavirin (used in the treatment of hepatitis C) commonly cause anemia, which usually precludes phlebotomy for PCT.

Attainment and maintenance of an iron-reduced state decreases the severity and progression of chronic hepatitis C and probably also reduces the risk of developing hepatocellular carcinoma [Ryan Caballes et al 2012].

Prevention of Primary Manifestations

Identification and avoidance of susceptibility factors (where applicable) is advised. See Agents/Circumstances to Avoid.

Vaccination against hepatitis A and B is appropriate.

Surveillance

It is advisable to follow porphyrin levels annually and resume phlebotomies (see Treatment of Manifestations) if porphyrin levels begin to rise in the presence of cutaneous signs. Note: Increase in urinary total porphyrins may also be caused by an increase in coproporphyrin (which is of no relevance with regard to the PCT); thus, when levels are only moderately increased, urinary porphyrin fractionation should be performed.

Because of reports of an association between diabetes mellitus and PCT [Muñoz-Santos et al 2011], annual screening with a fasting glucose level is recommended, particularly in those with hypertension (BP >135/80 mm Hg).

Hepatocellular cancer (HCC) surveillance relies on a combination of serum AFP determinations and hepatic ultrasonography. No guidelines as to the frequency of these tests are currently available due to the rarity of PCT and even rarer occurrence of HCC. Surveillance is usually performed annually; however, in those with advanced chronic hepatitis C and/or alcoholic cirrhosis, hepatologists generally agree that surveillance for HCC should be at least every six months.

Agents/Circumstances to Avoid

Avoid the following:

  • Susceptibility factors (if known) (e.g., iron supplements, alcohol consumption, smoking, oral estrogen use, and hepatotoxins such as hexachlorobenzene)
  • Exposure to sunlight in symptomatic phase

Evaluation of Relatives at Risk

Testing at-risk relatives of an individual with F-PCT to identify those with a UROD pathogenic variant is not expected to alter their management due to the low risk of development of the signs and symptoms of PCT. Nevertheless, if the family-specific UROD pathogenic variant is known, it is reasonable to clarify the genetic status of at-risk relatives so that those with a UROD pathogenic variant can avoid known susceptibility factors.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy is generally not complicated by F-PCT. Women with active F-PCT should be able to carry pregnancies to term [Aziz Ibrahim & Esen 2004, Tollånes et al 2011].

It is recommended that women with F-PCT be treated prior to the onset of planned pregnancies.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Familial porphyria cutanea tarda (F-PCT) is inherited in an autosomal dominant manner with reduced penetrance.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with F-PCT inherited a UROD pathogenic variant from a parent. However, few individuals diagnosed with F-PCT have a clinically affected parent because penetrance is significantly reduced.
  • A proband with F-PCT may have the disorder as the result of a de novo pathogenic variant; the proportion of cases caused by a de novo pathogenic variant is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing. Evaluation of parents may determine that an asymptomatic parent has a UROD pathogenic variant. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed on the parents of the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected or has a UROD pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, the likelihood of the sib developing F-PCT is small.

Offspring of a proband. Each child of an individual with F-PCT has a 50% chance of inheriting the UROD pathogenic variant. Because of reduced penetrance, the likelihood of offspring developing F-PCT is small.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected or has a UROD pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with type II PCT has a UROD pathogenic variant, the UROD pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with type II PCT.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the UROD pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • American Porphyria Foundation (APF)
    4900 Woodway
    Suite 780
    Houston TX 77056-1837
    Phone: 866-273-3635 (toll-free); 713-266-9617
    Fax: 713-840-9552
    Email: porphyrus@aol.com
  • European Porphyria Network
    Email: contact@porphyria.eu
  • Swedish Porphyria Patients' Association
    Karolinska Universitetssjukhuset
    Huddinge M 96
    Stockholm Stockholms Lan SE-141 86
    Sweden
    Phone: +46 8 711 56 09
    Email: porfyrisjukdomar@gmail.com
  • RDCRN Patient Contact Registry: Porphyrias Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Familial Porphyria Cutanea Tarda: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
UROD1p34​.1Uroporphyrinogen decarboxylaseUROD databaseURODUROD

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Familial Porphyria Cutanea Tarda (View All in OMIM)

176100PORPHYRIA CUTANEA TARDA
613521UROPORPHYRINOGEN DECARBOXYLASE; UROD

Gene structure. The UROD transcript reference sequence NM_000374.4 has ten exons. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. More than 100 different UROD pathogenic variants have been identified in individuals with familial porphyria cutanea tarda (F-PCT). F-PCT-related UROD pathogenic variants include missense (the most common), nonsense, and splice site variants; several small and large deletions; and small insertions [Anderson et al 2001].

Homozygosity for null alleles is lethal [Phillips et al 2007].

Two pathogenic variants, p.Arg193Pro and c.636+1G>C, account for 74% of pathogenic alleles in Norway. The p.Arg193Pro is a founder variant in this population [Aarsand et al 2009]. The p.Gly281Glu pathogenic variant is common in Spain [Gómez-Abecia et al 2013].

Table 3.

UROD Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.578G>Cp.Arg193ProNM_000374​.4
NP_000365​.3
c.636+1G>C
c.842G>Ap.Gly281Glu

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. UROD encodes the enzyme uroporphyrinogen decarboxylase (UROD). The protein encoded by the reference transcript has 367 amino acids (NP_000365.3) (see protein structure).

Abnormal gene product. Hepatic uroporphyrinogen decarboxylase enzyme activity less than approximately 20% of normal results in disease. Persons with F-PCT are heterozygous for a pathogenic variant that reduces UROD activity and immunoreactivity to approximately 50% of normal in all tissues. Persons with familial PCT are asymptomatic – despite having a baseline decreased UROD activity – until exposure to one or more susceptibility factors leads to increased oxidation and a subsequent further decrease of enzyme activity. Loss of enzyme activity results in accumulation of highly carboxylated porphyrins, which causes clinical features.

References

Literature Cited

  • Aarsand AK, Boman H, Sandberg S. Familial and sporadic porphyria cutanea tarda: characterization and diagnostic strategies. Clin Chem. 2009;55:795–803. [PubMed: 19233912]
  • Anderson KE, Goeger DE, Carson RW, Lee SM, Stead RB. Erythropoietin for the treatment of porphyria cutanea tarda in a patient on long-term hemodialysis. N Engl J Med. 1990;322:315–7. [PubMed: 2104958]
  • Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. In: Scriver CR, Beaudet AL, Valle D, Sly WS, Childs B, Kinzler KW, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:2961-2.
  • Aziz Ibrahim A, Esen UI. Porphyria cutanea tarda in pregnancy: a case report. J Obstet Gynaecol. 2004;24:574–5. [PubMed: 15369945]
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Suggested Reading

  • Bonkovsky HL, Hou W, Li T, Guo J-T, Narang T, Thapar M. Porphyrin and heme metabolism and the porphyrias. In: Lu S, Omary B, Wolkoff A, eds. Comprehensive Physiology. New York, NY: Wiley-Blackwell; 2012:365-401.
  • Phillips JD, Anderson KE. The porphyrias. In: Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Williams Hematology. 8 ed. New York, NY: McGraw-Hill; 2010:57-1-50.

Chapter Notes

Acknowledgments

On behalf of the Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network; including Dr. Karl Anderson, University of Texas Medical Branch, Galveston, TX; Dr. Montgomery Bissell, University of California, San Francisco, CA; Dr. Herbert Bonkovsky, Carolinas Medical Center, Charlotte, NC; Dr. John Phillips, University of Utah School of Medicine, Salt Lake City, UT

Revision History

  • 8 September 2016 (sw) Comprehensive update posted live
  • 22 August 2013 (me) Comprehensive update posted live; GeneReview divided into type II porphyria cutanea tarda and hepatoerythropoietic porphyria
  • 6 June 2013 (me) Review posted live
  • 26 April 2012 (hb) Original Submission
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