We report a patient homozygous for the UROD c.185C>T (p.P62L) variant who presents with clinical features resembling familial porphyria cutanea tarda (PCT). This case highlights the limitations of rigid UROD-related porphyria classifications and supports the existence of a phenotypic continuum modulated by genetic, epigenetic, and environmental factors. Hepatoerythropoietic porphyria (HEP) is characterized by blistering skin lesions, hypertrichosis, and scarring over the affected skin areas. Disease manifestations occur during infancy or childhood and with similar frequency in females and males. Mild anemia/hemolysis are not uncommon. The diagnosis of HEP is established in a proband with elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin), significantly increased erythrocyte zinc protoporphyrin, and/or biallelic pathogenic (or likely pathogenic) variants in UROD identified by molecular genetic testing. Treatment of manifestations: No treatment regimens can restore uroporphyrinogen decarboxylase (UROD enzyme levels in individuals with HEP. The mainstays of therapy are avoidance of sunlight (including the long-wave ultraviolet light sunlight that passes through window glass) by use of protective clothing and topical application of opaque sunscreens. On sun-exposed areas of the skin, bullous lesions develop that require prompt management of resultant skin infections when appropriate. Phlebotomy and chloroquine, which are usually effective in treating the allelic disorder familial porphyria cutanea tarda, are generally ineffective in individuals with HEP. Agents/circumstances to avoid: Exposure to sunlight in persons of all ages. Older individuals should avoid known susceptibility factors: alcohol, oral estrogen, iron overload, smoking, and drugs that induce the cytochrome P450s. Evaluation of relatives at risk: If the family-specific UROD pathogenic variants are known, it is reasonable to clarify the genetic status of at-risk relatives so that those with biallelic UROD pathogenic variants can be counseled regarding sun protection and avoidance of known susceptibility factors. HEP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a UROD pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic UROD pathogenic variants and having HEP, a 50% chance of inheriting one pathogenic variant and having familial porphyria cutanea tarda, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the UROD pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. 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). 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. 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. 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.

Clinically manifest porphyria cutanea tarda (PCT) is a rare condition in childhood; however, several cases have been reported in the literature and at our centre. Porphyria Center Sweden is a national knowledge centre, and since 1987, we have diagnosed approximately 1400 new cases of manifest PCT, of which only five have been children. All children have been identified as heterozygous carriers of a pathogenic UROD gene variant and homozygous for hemochromatosis. In our experience, the diagnosis of children with PCT has been delayed, even in the presence of cutaneous symptoms, without known family history. In this case report, and in another child from our centre, the disease has been suspected due to reddish discolored urine in the absence of cutaneous symptoms. In these two cases, the mothers associated the beetroot red urine with known cases of PCT in the family history. The remaining three cases documented in this report were diagnosed based on cutaneous symptoms.

We report a case of 33-year-old female with underlying genetic susceptibility for familial porphyria cutanea tarda due to novel UROD variant (c.636 + 2 dupT) unmasked by transient exposure to supraphysiological oestrogen concentrations following a single cycle of successful controlled ovarian stimulation for oocyte retrieval. Use of oral oestrogen in the form of oral contraceptive pills and hormone replacement therapy has been well known to trigger active porphyria cutanea tarda phenotype in susceptible women. However, to date, the emergence of clinically overt porphyria cutanea tarda has not been reported in association with fertility treatment in the literature before.