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 with elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin) and a heterozygous pathogenic variant in UROD identified by molecular genetic testing.

Management.

Treatment of manifestations: No treatment regimens can restore UROD enzyme levels in individuals with F-PCT. The mainstays of therapy are reduction of body iron stores and liver iron content, and use of low-dose antimalarial agents (hydroxychloroquine). In addition, modifiable risk factors can be addressed by ceasing alcohol/tobacco use, modifying estrogen use, and treating hepatitis C infection (if present).

Surveillance: Monitor urinary porphyrin levels annually. For those who have been treated by phlebotomy, resume iron reduction by therapeutic phlebotomies if and when urinary uroporphyrins and heptacarboxylporphyrins increase to greater than 400 µg/g creatinine. Monitor for diabetes mellitus annually with fasting glucose, particularly in individuals with hypertension. Monitor for HCC annually with serum AFP concentration and hepatic ultrasonography; monitor every six months in those with cirrhosis.

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

Evaluation of relatives at risk: 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.

Genetic counseling.

F-PCT is inherited in an autosomal dominant manner with reduced penetrance. Most individuals diagnosed with F-PCT inherited a UROD pathogenic variant from a heterozygous, asymptomatic parent. Each child of an individual with F-PCT has a 50% chance of inheriting the UROD pathogenic variant; because the penetrance of F-PCT is low, the likelihood of offspring developing signs and symptoms of PCT is small. Once the UROD pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. However, because of the low penetrance of F-PCT, the results of prenatal testing are not useful in accurately predicting whether an individual with one UROD pathogenic variant will develop clinical manifestations of PCT.

Suggestive Findings

Familial porphyria cutanea tarda (F-PCT) should be suspected in a proband with the following clinical findings and suggestive biochemical findings. In some, there may also be a family history of PCT, although this is far from universal.

Clinical features (typically developing in the 5th-6th decade):

• Photosensitivity resulting in fluid-filled vesicles, bullae, blisters, and sores 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). Because the blister fluid is high in porphyrin content, it may appear pink to red. Upon rupturing, these lesions can crust over, heal slowly, and result in secondary infection.
• 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 progressive systemic sclerosis

Biochemical findings

• Increased urine or plasma total porphyrins (first-line testing; sensitive, not specific)
• Fractionate urine porphyrins showing a predominance of uroporphyrin & heptacarboxylporphyrin (second-line testing)
  See Table 1 for the complete biochemical profile of F-PCT.
• Normal or minimally increased urine delta-aminolevulinic acid levels
• In some persons with severe F-PCT, pink-appearing urine that fluoresces bright pink when excited by long UV-blue light

Family history may suggest autosomal dominant inheritance (e.g., an affected parent) or may not reveal other affected family members because of the low penetrance of clinical manifestations of PCT that result in a significant proportion of heterozygotes remaining asymptomatic (see Penetrance).

Establishing the Diagnosis

The diagnosis of familial porphyria cutanea tarda (F-PCT) is established in a proband with elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin) (see Table 1) and a heterozygous pathogenic (or likely pathogenic) variant in UROD identified by molecular genetic testing (see Table 2).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous UROD variant of uncertain significance does not establish or rule out the diagnosis of the disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (Option 1), whereas genomic testing does not (Option 2).

Clinical Description

Familial porphyria cutanea tarda (F-PCT) is characterized by cutaneous findings including skin friability and chronic blistering over sun-exposed areas (classically the dorsal aspects of the hands). In contrast to the acute hepatic porphyrias or erythropoietic cutaneous porphyrias, F-PCT does not manifest as acute episodes of pain or acute/painful skin changes upon sun exposure, respectively. Hepatic involvement of F-PCT is characterized by elevation in aminotransferases, increased iron stores, and varying degrees of fibrosis accompanied by an increased risk for hepatocellular carcinoma.

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, secondary infection of ruptured blisters, facial hypertrichosis and hyperpigmentation, and severe thickening of the affected skin areas (pseudoscleroderma) that resembles systemic scleroderma.

Histopathology of the skin in F-PCT demonstrates subepidermal fluid collections (blistering), hyperkeratosis, and lipid proteinosis. Additional findings can include deposition of PAS-positive material around blood vessels and fine fibrillar material in the upper dermis, as well as splitting of the lamina lucida of the basement membrane at the dermoepithelial junction [Dabski & Beutner 1991]. These findings are not diagnostic of F-PCT and can be found in other cutaneous porphyrias, pseudoporphyria, and other disorders.

Hepatic involvement commonly manifests as elevated serum aminotransferase levels and gamma glutamyl transpeptidase.

Some affected individuals will demonstrate evidence of hepatic iron overload, suggested by elevated serum ferritin concentration and elevated transferrin saturation.

While cirrhosis may develop in 30%-40% of individuals, predisposing factors are concomitant infection with hepatitis C virus and use of alcohol.

The risk for hepatocellular carcinoma is increased in individuals with F-PCT, especially in those with other risk factors predisposing to advanced liver disease (see Pathophysiology) [Cassiman et al 2008, Baravelli et al 2019].

Pathophysiology

Development of clinical manifestations of familial porphyria cutanea tarda (F-PCT) requires both heterozygosity for a UROD pathogenic variant that results in approximately 50% reduction of the activity of the enzyme uroporphyrinogen decarboxylase (UROD) and the presence of other susceptibility factors that generate an inhibitor that reduces UROD activity to less than 20% of normal. When the hepatic enzyme UROD is significantly inhibited, oxidized porphyrins (mostly uroporphyrin and heptacarboxylporphyrin) that accumulate in the liver are transported from the hepatocytes into the plasma and eventually into the urine. These excess plasma porphyrins may also be deposited in the skin and other tissues.

Genotype-Phenotype Correlations

No UROD genotype-phenotype correlations are known.

Presence of biallelic null variants is lethal [Phillips et al 2007].

Nomenclature

Porphyria cutanea tarda (PCT) that is not associated with a UROD pathogenic variant is referred to as type I PCT or sporadic PCT [Bonkovsky et al 2013] (see Differential Diagnosis).

F-PCT (i.e., porphyria cutanea tarda caused by a heterozygous pathogenic variant in UROD) may also be referred to as "UROD-related porphyria cutanea tarda" based on the naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Penetrance

The penetrance of F-PCT is low, given that in addition to heterozygosity for a UROD pathogenic variant, other susceptibility factors need to be present (see Pathophysiology, Susceptibility Factors).

Prevalence

The prevalence of F-PCT is approximately 8:1,000,000 (based on the estimated prevalence of PCT as 40:1,000,000 and of F-PCT as ~20% of PCT) [Merk 2016].

Other Disorders in the Differential Diagnosis of F-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 nongalvanized steel drums.

Pseudoporphyria. Although the skin histopathologic findings of pseudoporphyria are indistinguishable from those of PCT, pseudoporphyria is not associated with porphyrin biochemical abnormalities. Drugs implicated in the pathogenesis of this immune-mediated condition include photosensitizing agents such as nonsteroidal anti-inflammatory drugs, tetracycline, voriconazole, loop/thiazide diuretics, retinoids, imatinib, and simvastatin [Gil-Lianes et al 2022]. Host genetic factors are likely also involved. The cause(s) of pseudoporphyria can be difficult to ascertain, and the disease can be long-lasting.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with familial porphyria cutanea tarda (F-PCT), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Evaluation of 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)
• Medical history regarding susceptibility factors that are known to influence the presence and/or severity of clinical manifestations (see Pathophysiology, Susceptibility Factors). When warranted, evaluation for medical findings that could influence occurrence and severity of cutaneous manifestations, including the following:
  • Presence of HFE pathogenic variants that lead to iron loading (identified by molecular genetic testing; see HFE Hemochromatosis.)
  • Excess iron based on iron indices: serum ferritin level; serum iron concentration, total iron binding capacity, and percent iron saturation
  • Alcohol consumption
  • Tobacco use
  • Oral estrogen use
  • Chronic kidney disease / end-stage kidney disease
  • Presence of hepatitis C and/or human immunodeficiency virus infection
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of F-PCT in order to facilitate medical and personal decision making

Treatment of Manifestations

There are no effective treatment regimens to restore UROD enzyme levels in individuals with F-PCT.

The mainstays of therapy for PCT that are highly effective in individuals with F-PCT are:

• Reduction of body iron stores and liver iron content;
• Use of low-dose antimalarial agents (hydroxychloroquine).

In addition, addressing modifiable risk factors such as ceasing alcohol/tobacco use, modifying estrogen use, and treatment of hepatitis C infection, if present, is warranted.

Surveillance

Monitor urinary porphyrin levels annually. For those who have been treated by phlebotomy, resume iron reduction by therapeutic phlebotomies if and when urinary uroporphyrins and heptacarboxylporphyrins increase to greater than 400 µg/g creatinine (see Treatment of Manifestations) to prevent recurrence of cutaneous signs. Note: Increase in urinary total porphyrins may also be caused by an increase in coproporphyrin (which is not relevant to F-PCT); thus, when urinary porphyrin 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 (blood pressure >135/80 mm Hg).

Hepatocellular cancer (HCC) surveillance relies on a combination of serum alpha-fetoprotein determinations and hepatic ultrasonography or cross-sectional imaging (CT or MRI). No guidelines as to the frequency of these tests are currently available because of the rarity of F-PCT and even rarer occurrence of HCC. Surveillance is usually performed annually; however, in those with 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, estrogen use, and hepatotoxins such as hexachlorobenzene) (See Pathophysiology, Susceptibility Factors.)
• Exposure to sunlight in symptomatic phase (i.e., when new skin changes appear)

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 because of the low penetrance, and hence low risk of development of the signs and symptoms of F-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 Pathophysiology, Susceptibility Factors).

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

Pregnancy Management

Women with active F-PCT should be able to carry pregnancies to term, though the pregnancy should be considered "high risk" and followed by an appropriately qualified obstetrician [Aziz Ibrahim & Esen 2004, Tollånes et al 2011].

It is recommended that women with F-PCT and iron overload (which is rather unusual in women during their child-bearing years) be treated to reduce body iron stores prior to the onset of planned pregnancies (see Treatment of Manifestations).

The use of hydroxychloroquine during human pregnancy is not thought to lead to adverse fetal effects.

The use of chloroquine at higher doses has produced adverse embryonic effects in animal pregnancies; however, case reports of low doses of chloroquine used in human pregnancy for rheumatic disease have not been associated with adverse fetal outcomes. The US FDA recommends that chloroquine or hydroxychloroquine not be used in pregnant or lactating women unless the expected benefit outweighs the possible risks. No formal grade for use in such women has been assigned.

While iron chelation therapy is not a treatment of choice, some pregnant women may be taking an iron chelator at the time of conception or during pregnancy.

• Data on the use of deferoxamine during human pregnancy suggest that it is not likely to cause adverse fetal effects.
• Data on use of deferasirox during human pregnancy are more limited, although reassuring.
• Data on the use of deferiprone during human pregnancy are very limited.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

A Phase II open-label trial (NCT03118674) is studying the effect of treating individuals with porphyria cutanea tarda (PCT) and hepatitis C with direct-acting antiviral agents as the sole therapy (i.e., no phlebotomy or low-dose hydroxychloroquine). However, it is noted that the effect of this approach on the disease course of F-PCT is less clear.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

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

Note: The penetrance of F-PCT is low, given that in addition to heterozygosity for a UROD pathogenic variant, other susceptibility factors need to be present (see Pathophysiology, Susceptibility Factors).

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with F-PCT inherited a UROD pathogenic variant from a heterozygous, asymptomatic parent. Few individuals diagnosed with F-PCT have a clinically affected parent because penetrance is low.
• Some individuals diagnosed with F-PCT have the disorder as the result of a de novo pathogenic variant; however, the proportion of probands who have a de novo pathogenic variant is unknown.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed may appear to be negative because of the low penetrance F-PCT in heterozygous individuals. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in 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 and/or is known to have the UROD pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because development of clinical manifestations of F-PCT requires both heterozygosity for a UROD pathogenic variant and the presence of other susceptibility factors, the likelihood that a sib who inherits a UROD pathogenic will develop signs and symptoms of PCT is small (see Pathophysiology).
• If the proband has a known UROD pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

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

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected and/or has a UROD pathogenic variant, members of the parent's family 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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 F-PCT.

Prenatal Testing and Preimplantation Genetic Testing

Once the UROD pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. However, because of the low penetrance of F-PCT, the results of prenatal testing are not useful in accurately predicting whether an individual with one UROD pathogenic variant will develop clinical manifestations of PCT.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

UROD encodes the enzyme uroporphyrinogen decarboxylase (UROD). Although persons with familial porphyria cutanea tarda (F-PCT) are heterozygous for a pathogenic variant that reduces UROD activity in all tissues to approximately 50% of normal, they remain asymptomatic until exposure to one or more susceptibility factors that generate an inhibitor reduces UROD activity to less than 20% of normal (see Pathophysiology). Hepatic enzyme activity below a certain critical threshold results in accumulation of highly carboxylated porphyrins (mostly uroporphyrin and heptacarboxylporphyrin) in the liver, which are then transported out of hepatocytes and appear in the plasma, urine, and feces. These excess plasma porphyrins are deposited in the skin and other tissues. Porphyrins in the skin and microcapillaries of the skin are activated when exposed to light, releasing reactive oxygen species that further damage the surrounding tissue, resulting in the observed cutaneous manifestations.

Mechanism of disease causation. Loss of function

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 Bruce Wang, University of California, San Francisco, CA; Drs Herbert Bonkovsky and Sean Rudnick, Atrium Health Wake Forest Baptist, Winston-Salem, NC; Dr John Phillips, University of Utah School of Medicine, Salt Lake City, UT; Drs Brendan McGuire and Mohamed Kazamel, Univ of Alabama at Birmingham, Birmingham, AL; Drs Manisha Balwani and Robert Desnick, Icahn School of Medicine at Mt Sinai, New York, NY; and the United Porphyria Association.

Author History

Herbert Bonkovsky, MD (2013-present)
Lawrence U Liu, MD; Icahn School of Medicine at Mount Sinai (2013-2022)
John Phillips, PhD (2013-present)
Sean Rudnick, MD (2022-present)

Revision History

• 9 June 2022 (bp) Comprehensive update posted live
• 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

Literature Cited

• Aziz Ibrahim A, Esen UI. Porphyria cutanea tarda in pregnancy: a case report. J Obstet Gynaecol. 2004;24:574–5. [PubMed: 15369945]
• Baravelli CM, Sandberg S, Aarsand A, Tollanes M. Porphyria cutanea tarda increases risk of hepatocellular carcinoma and premature death: a nationwide cohort study. Orphanet J Rare Dis. 2019;14:77. [PMC free article: PMC6448269] [PubMed: 30944007]
• Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, Bennett JT, Bird LM, Carey JC, Chung B, Clark RD, Cox TC, Curry C, Dinulos MBP, Dobyns WB, Giampietro PF, Girisha KM, Glass IA, Graham JM Jr, Gripp KW, Haldeman-Englert CR, Hall BD, Innes AM, Kalish JM, Keppler-Noreuil KM, Kosaki K, Kozel BA, Mirzaa GM, Mulvihill JJ, Nowaczyk MJM, Pagon RA, Retterer K, Rope AF, Sanchez-Lara PA, Seaver LH, Shieh JT, Slavotinek AM, Sobering AK, Stevens CA, Stevenson DA, Tan TY, Tan WH, Tsai AC, Weaver DD, Williams MS, Zackai E, Zarate YA. A dyadic approach to the delineation of diagnostic entities in clinical genomics. Am J Hum Genet. 2021;108:8–15. [PMC free article: PMC7820621] [PubMed: 33417889]
• Bonkovsky HL, Hou W, Li T, Guo J-T, Narang T, Thapar M. Porphyrin and heme metabolism and the porphyrias. Compr Physiol. 2013;3:365–401. [PubMed: 23720291]
• Cassiman D, Vannoote J, Roelandts R, Libbrecht L, Roskams T, Van den Oord J, Fevery J, Garmyn M, Nevens F. Porphyria cutanea tarda and liver disease: A retrospective analysis of 17 cases from a single centre and review of the literature. Acta Gastroenterol Belg. 2008;71:237–42. [PubMed: 18720935]
• Dabski C, Beutner EH. Studies of laminin and type IV collagen in blisters of porphyria cutanea tarda and drug-induced pseudoporphyria. J Am Acad Dermatol. 1991;25:28–32. [PubMed: 1880250]
• Desai T, Bortman J, Al-Sibae R, Bonkovsky HL. The role of iron in hepatitis C infection. Curr Hepat Rep. 2012;11:41–7.
• Gil-Lianes J, Luque-Luna M, Morgado-Carrasco D, Aguilera-Peiró P. Pseudoporphyria-a diagnostic challenge: a case series and a proposed diagnostic algorithm. Photodermatol Photoimmunol Photomed. 2022. Epub ahead of print. [PubMed: 35165937]
• Jalil S, Grady JJ, Lee C, Anderson KE. Associations among behavior-related susceptibility factors in porphyria cutanea tarda. Clin Gastroenterol Hepatol. 2010;8:297–302. [PMC free article: PMC2834813] [PubMed: 19948245]
• Merk HF. Porphyria cutanea tarda. Hautarzt. 2016;67:207–10. [PubMed: 26743054]
• Muñoz-Santos C, Guilabert A, Moreno N, Gimenez M, Darwich E, To-Figueras J, Herrero C. The association between porphyria cutanea tarda and diabetes mellitus: analysis of a long-term follow-up cohort. Br J Dermatol. 2011;165:486–91. [PubMed: 21564073]
• Muñoz-Santos C, Guilabert A, Moreno N, To-Figueras J, Badenas C, Darwich E, Herrero C. Familial and sporadic porphyria cutanea tarda: clinical and biochemical features and risk factors in 152 patients. Medicine (Baltimore). 2010;89:69–74. [PubMed: 20517178]
• Phillips JD, Bergonia HA, Reilly CA, Franklin MR, Kushner JP. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc Natl Acad Sci U S A. 2007;104:5079–84. [PMC free article: PMC1820519] [PubMed: 17360334]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Ratnaike S, Blake D, Campbell D, Cowen P, Varigos G. Plasma ferritin levels as a guide to the treatment of porphyria cutanea tarda by venesection. Australas J Dermatol. 1988;29:3–8. [PubMed: 3250437]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rocchi E, Casalgrandi G, Masini A, Giovannini F, Ceccarelli D, Ferrali M, Marchini S, Ventura E. Circulating pro- and antioxidant factors in iron and porphyrin metabolism disorders. Ital J Gastroenterol Hepatol. 1999;31:861–7. [PubMed: 10669994]
• Rocchi E, Gibertini P, Cassanelli M, Pietrangelo A, Borghi A, Ventura E. Serum ferritin in the assessment of liver iron overload and iron removal therapy in porphyria cutanea tarda. J Lab Clin Med. 1986;107:36–42. [PubMed: 3941293]
• Rodrigues N, Caeiro F, Santana A, Mendes T, Lopes L. Porphyria cutanea tarda in a patient with end-stage renal disease: A case of successful treatment with deferoxamine and ferric carboxymaltose. Case Rep Nephrol. 2017;2017:4591871. [PMC free article: PMC5292176] [PubMed: 28210512]
• Ryan Caballes F, Sendi H, Bonkovsky HL. Hepatitis C, porphyria cutanea tarda and liver iron: an update. Liver Int. 2012;32:880–93. [PMC free article: PMC3418709] [PubMed: 22510500]
• Shieh S, Cohen JL, Lim HW. Management of porphyria cutanea tarda in the setting of chronic renal failure: a case report and review. J Am Acad Dermatol. 2000;42:645–52. [PubMed: 10727312]
• Sinclair PR, Gorman N, Shedlofsky SI, Honsinger CP, Sinclair JF, Karagas MR, Anderson KE. Ascorbic acid deficiency in porphyria cutanea tarda. J Lab Clin Med. 1997;130:197–201. [PubMed: 9280147]
• Singal AK, Kormos-Hallberg C, Lee C, Sadagoparamanujam VM, Grady JJ, Freeman DH Jr, Anderson KE. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol. 2012;10:1402–9. [PMC free article: PMC3501544] [PubMed: 22985607]
• Smith AG, Elder GH. Complex gene-chemical interactions: hepatic uroporphyria as a paradigm. Chem Res Toxicol. 2010;23:712–23. [PubMed: 20099833]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Tollånes MC, Aarsand AK, Sandberg S. Excess risk of adverse pregnancy outcomes in women with porphyria: a population-based cohort study. J Inherit Metab Dis. 2011;34:217–23. [PMC free article: PMC3026662] [PubMed: 20978938]
• Weiss Y, Chen B, Yasuda M, Nazarenko I, Anderson KE, Desnick RJ. Porphyria cutanea tarda and hepatoerythropoietic porphyria: identification of 19 novel uroporphyrinogen III decarboxylase mutations. Mol Genet Metab. 2019;128:363–6. [PMC free article: PMC8132452] [PubMed: 30514647]