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 an uncommon autosomal recessive disorder marked by deficiencies in enzymes involved in heme biosynthesis. This results in the build-up of porphyrins and their precursors. Here, we describe a case study of a 17-year-old male who has experienced symptoms of porphyria since early childhood. The patient exhibited initial symptoms of porphyria, including dark-coloured urine, abdominal pain, constipation and cutaneous lesions. Genetic testing at age 17 confirmed a homozygous mutation in the UROD gene, diagnosing HEP. Additional mutations in the CNGB1 and BTD genes contributed to retinitis pigmentosa and biotinidase deficiency, respectively. The patient also experienced complications such as thumb amputation and finger developmental anomalies. This case underscores the diagnostic challenges and multidisciplinary management required for patients with complex genetic profiles and rare porphyria subtypes such as HEP. Further research is essential to enhance understanding and treatment strategies for such intricate genetic conditions. This is a first report of hepatoerythropoietic porphyria with coexisting BTD and CNGB1 genetic mutations.

Hepatic porphyrias are a group of metabolic disorders that are characterized by overproduction and accumulation of porphyrin precursors in the liver. These porphyrins cause neurologic symptoms as well as cutaneous photosensitivity, and in some cases patients can experience life-threatening acute neurovisceral attacks. This review describes the acute hepatic porphyrias in detail, including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, as well as the hepatic porphyrias with cutaneous manifestations such as porphyria cutanea tarda and hepatoerythropoietic porphyria. Each section will cover disease prevalence, clinical manifestations, and current therapies, including strategies to manage symptoms. Finally, we review new and emerging treatment modalities, including gene therapy through use of adeno-associated vectors and chaperone therapies such as lipid nanoparticle and small interfering RNA-based therapeutics. Porphyrias are a spectrum of metabolic disorders arising from a defect or alteration of enzymes in the heme biosynthesis pathway which present with either neurovisceral symptoms, cutaneous symptoms, or a combination of the two. Porphyria cutanea tarda (PCT), the most common porphyria, is the result of a deficiency of the enzyme uroporphyrinogen decarboxylase (UROD). The hallmark of this disorder is photosensitivity. Hepatic UROD is tasked with the conversion of uroporphyrinogen III to coproporphyrinogen III, and failure to do so results in the accumulation of the preceding compounds in the liver that eventually appears in the plasma and urine.  Hepatoerythropoietic porphyria (HEP) is another rare form of porphyria which is clinically very similar to PCT but occurs due to homozygous mutation of UROD genes, whereas in PCT, the mutation in UROD gene, when present, is usually heterozygous. In this article, we discuss the different causes of UROD deficiency, along with clinically pertinent information for diagnosing and managing patients with PCT. 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.

The porphyrias are a group of metabolic disorders resulting from an innate abnormality in haem biosynthesis, and the clinical settings of which vary according to the genetic enzyme abnormality in question. These are genetic disorders with autosomal dominant or recessive inheritance of varying penetrance, and whose clinical expression differs according to the preferential location of haem precursors. Different classifications have been proposed according to genetic inheritance, the enzyme anomaly at issue, and clinical expression. The clinical classification distinguishes between acute porphyria (acute intermittent porphyria, porphyria variegata, hereditary coproporphyria), bullous cutaneous porphyrias (porphyria cutanea tarda, porphyria variegata and hereditary coproporphyria), painful photosensitive acute cutaneous porphyrias (erythropoietic protoporphyria and X-linked dominant protoporphyria), and rare recessive porphyrias (congenital erythropoietic porphyria, Doss porphyria, hepatoerythropoietic porphyria and harderoporphyria). Treatment depends on the clinical expression of the disorder.

Porphyria Cutanea Tarda (PCT) is a cutaneous porphyria that results from the hepatic inhibition of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD), and can occur either in the absence or presence of an inherited heterozygous UROD mutation (PCT subtypes 1 and 2, respectively). A heterozygous UROD mutation causes half-normal levels of UROD activity systemically, which is a susceptibility factor but is not sufficient alone to cause type 2 PCT. In both Types 1 and 2 PCT, the cutaneous manifestations are precipitated by additional factors that lead to generation of an inhibitor that more profoundly reduces hepatic UROD activity. PCT is an iron-related disorder, and many of its known susceptibility factors, which include infections (e.g. hepatitis C virus, HIV), high alcohol consumption, smoking, estrogens, and genetic traits (e.g. hemochromatosis mutations) can increase hepatic iron accumulation. Hepatoerythropoietic Porphyria (HEP) is a rare autosomal recessive disease that results from homozygosity or compound heterozygosity for UROD mutations and often causes infantile or childhood onset of both erythropoietic and cutaneous manifestations. During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for 387 unrelated patients with PCT and four unrelated patients with HEP. Of the 387 unrelated individuals tested for Type 2 PCT, 79 (20%) were heterozygous for UROD mutations. Among 26 family members of mutation-positive PCT patients, eight (31%) had the respective family mutation. Additionally, of the four unrelated HEP patients referred for UROD mutation analyses, all had homozygosity or compound heterozygosity for UROD mutations, and all eight asymptomatic family members were heterozygotes for UROD mutations. Of the UROD mutations identified, 19 were novel, including nine missense, two nonsense, one consensus splice-site, and seven insertions and deletions. These results expand the molecular heterogeneity of PCT and HEP by adding a total of 19 novel UROD mutations. Moreover, the results document the usefulness of molecular testing to confirm a genetic susceptibility trait in Type 2 PCT, confirm a diagnosis in HEP, and identify heterozygous family members.