3.1 Erythropoietic Protoporphyria (EPP)3.1.1 Pathobiology

Erythropoietic protoporphyria is a non-blistering cutaneous porphyria caused by a deficiency of FECH, the final enzyme in the heme biosynthesis pathway that inserts ferrous iron into protoporphyrin IX (PPIX) to make heme [7, 11]. Erythropoietic protoporphyria is characterized by the accumulation of metal-free PPIX in erythrocytes, plasma, and the skin due to erythroid production of PPIX exceeding FECH capacity for conversion [11, 12]. The highly photosensitizing PPIX is lipophilic and readily moves from red blood cells into subcutaneous tissue [1]. Following sunlight exposure, PPIX absorbs visible light and ultraviolet A radiation to form reactive oxygen species, damaging endothelial and subcutaneous tissues and triggering inflammatory responses [7, 13, 14]. This phototoxic mechanism is the basis of the acute painful non-blistering photosensitivity that defines EPP. Although most reactions are precipitated by natural sunlight, these phototoxic episodes may also occur with artificial light sources that emit wavelengths capable of activating PPIX, such as those used in surgical or dental procedures [1].

3.1.2 Inheritance and Epidemiology

Erythropoietic protoporphyria most commonly results from a pathogenic FECH variant on one allele and is typically inherited in an autosomal dominant pattern with incomplete penetrance [15]. Less commonly, EPP may also be inherited in an autosomal recessive pattern when biallelic pathogenic FECH variants are present [15]. A French cohort study found the prevalence of autosomal dominant EPP as 95% (95% confidence interval 91–99), whereas the prevalence of autosomal recessive EPP was 4% (95% confidence interval 1–8). In 97.9% of patients with EPP with autosomal dominant inheritance, a pathogenic FECH variant on one allele was inherited in trans with a common hypomorphic IVS3-48C allele that affects aberrant splicing and reduces FECH activity [15]. Another cohort study found that the IVS3-48C allele modulated the phenotypic expression of EPP in South African patients with EPP when compared with matched controls [16]. Clinical manifestations of dominant EPP occur when FECH activity falls below the expected 50%, underscoring the role of gene polymorphisms, such as IVS3-48C, in the clinical expression of EPP [17]. Accordingly, the clinical prevalence of EPP reflects the geographic distribution of the hypomorphic IVS3-48C allele, with a higher prevalence reported in Europe, North America, Japan, and southeast Asia, and a lower prevalence reported in West Africa [15]. As such, differences in the frequency of gene polymorphisms, along with potential protective effects of increased eumelanin levels, may contribute to these observed epidemiologic patterns [1, 15].

3.1.3 Clinical Features

Clinically, EPP presents in early childhood, with prodromal symptoms including tingling, burning, and itch of sun-exposed skin following minutes of sun exposure [1] (Table 1). With continued sun exposure, these symptoms can progress to severe phototoxic reactions characterized by erythema, purpura, and edema, and severe recalcitrant pain often affecting the hands, face, and feet [7] (Fig. 2). Unlike the blistering seen in VP, HCP, CEP, PCT, or HEP, EPP is characterized as non-blistering, although blistering may occur in severe reactions and is less common [1]. This photosensitivity may lead to hyperkeratosis, lichenification, and scarring of sun-exposed skin over time [1]. With repeated phototoxic reactions, patients may develop characteristic cobblestone-like changes of the nasal bridge and knuckles, reflecting chronic cutaneous injury [1]. Erythropoietic protoporphyria carries significant risks for anemia and iron deficiency, likely due to the complex interplay between impaired heme biosynthesis from FECH deficiency and reduced iron absorption and supply [8]. The risk of protoporphyric liver damage is also increased, as the hydrophobic nature of protoporphyrins causes excretion through bile and subsequent accumulation of protoporphyrin in the liver rather than urine, leading to hepatic dysfunction [11]. The accumulation of protoporphyrins in the liver results in liver failure in 2–5% of cases [18]. In addition, increased biliary excretion of protoporphyrin predisposes patients to cholelithiasis, which may necessitate a cholecystectomy. A prospective cohort study found that 22.1% of patients with EPP had gallstones, and 86.7% of those patients had undergone a cholecystectomy [18].

Table 1 Summary of key characteristics, diagnosis, and management of cutaneous porphyriasFig. 2

Linear erosions affecting the lateral nasal bridge and lower lip in a patient with erythropoietic protoporphyria. Clinical photograph courtesy of Horner et al. [53]

3.1.4 Diagnosis

Diagnosis of EPP relies on biochemical confirmation of markedly elevated total erythrocyte protoporphyrins approximately three to four times the upper limit of normal, with 85–100% present as metal-free protoporphyrin [12]. The remaining fraction is metal chelated, whereas XLP is distinguished by a lower metal-free proportion, typically 50–85% [19]. Given that protoporphyrin is not water soluble, excess protoporphyrin is excreted into bile and feces rather than urine; therefore, urinary protoporphyrin levels remain normal, whereas stool protoporphyrin levels may be increased but should not be used as a diagnostic criterion [11]. Direct measurement of whole-blood metal-free PPIX has been used in clinical trial settings but its utility in routine clinical diagnosis remains limited [20]. Genetic testing of FECH helps confirm the diagnosis and distinguish EPP from XLP, though the presence of unknown variants means that a negative genetic result cannot completely exclude EPP [11, 19].

3.1.5 Treatment and Management

Treatment and management of EPP focus on photoprotection and sun avoidance, prevention of hepatic complications, and improvement of functional quality of life. Broad-spectrum or tinted sunscreens with visible light blockers can help minimize phototoxic injury, but sun avoidance and photoprotective clothing are historically the most effective options [7]. Smaller studies, case series, and uncontrolled trials have evaluated additional therapeutic approaches, including ultraviolet phototherapy and beta carotene supplementation [21]. These interventions have not been studied in large randomized clinical trials, and reported outcomes have been variable [21]. In addition, cimetidine for protoporphyria has been evaluated in a phase II clinical trial; however, evidence supporting its clinical use remains limited, as prior reports are primarily case series suggesting potential improvements in PPIX levels and phototolerance, with no comparative studies demonstrating efficacy [11, 22]. Afamelanotide, a synthetic α-melanocyte stimulating hormone agonist delivered via a subcutaneous implant, has emerged as a key therapy approved by the US Food and Drug Administration for EPP and XLP, upregulating eumelanin production and antioxidant activity and limiting photoactive protoporphyrin activity [1, 23]. Additionally, dersimelagon is an oral, selective, melanocortin 1 receptor agonist currently under phase III clinical development that has demonstrated significant improvements in the duration of symptom-free sun exposure in patients with EPP or XLP [11, 24]. Bitopertin, an oral erythroid glycine transporter-1 inhibitor in phase II clinical development, has also shown a marked reduction in PPIX in erythroid cells and patients with EPP [20, 25]. Liver transplantation is warranted when disease progresses to liver failure, and bone marrow transplantation is curative in EPP but is generally reserved for severe hepatic disease or following liver transplantation to prevent EPP recurrence [7, 26]. Hepatitis A and B vaccinations are also advised to avoid preventable liver damage [11]. Transient elastography, a non-invasive ultrasound-based procedure, may be considered to assess patients with EPP at risk for severe hepatic disease by evaluating for cirrhosis, fibrosis, and steatosis without the need for a liver biopsy [27]. Given the increased risk of anemia and hepatic dysfunction, there should be regular monitoring of hemoglobin, iron, erythrocyte protoporphyrin levels, as well as liver function [8, 18]. For patients with EPP who have symptoms of iron deficiency anemia and/or have hemoglobin less than 10 g/dL and ferritin less than 10 μg/L, supplemental iron may be considered [19]. Patients with protoporphyria are also at increased risk of vitamin D deficiency because of sun avoidance; vitamin D supplementation and routine screening for vitamin D deficiency are advised [19].

3.2 X-Linked Protoporphyria3.2.1 Pathobiology

X-linked protoporphyria is a non-blistering cutaneous porphyria caused by gain-of-function mutations in the erythroid-specific 5-aminolevulinate synthase 2 (ALAS2) gene, which encodes the first and rate-limiting enzyme of the erythroid heme biosynthesis pathway [28, 29]. Increased activity of ALAS2 results in excessive production of early heme precursors such as PPIX, exceeding the downstream capacity of FECH [5]. While FECH is functionally normal in XLP, the disproportionate flux through the pathway causes FECH to be functionally rate limiting [30]. Consequently, large quantities of metal-free PPIX accumulate in erythrocytes and plasma, as well as in cutaneous and hepatic tissues [12, 18]. Although the production of PPIX exceeds FECH’s enzymatic capacity, the proportion of metal-free protoporphyrins is lower compared with EPP [19, 28].

3.2.2 Inheritance and Epidemiology

X-linked protoporphyria is inherited in an X-linked dominant pattern and characterized in male individuals by non-blistering photosensitivity, while heterozygous female individuals show variable expressivity depending on the pattern of X-chromosome inactivation within erythroid progenitors [31, 32]. A large North American cohort study found that male patients with XLP had a mean age of symptom onset of 2.7 years compared with 4.1 years in EPP, suggesting an earlier symptom onset compared with EPP [18].

3.2.3 Clinical Features

X-linked protoporphyria and EPP share overlapping phototoxic symptoms [33]. As with EPP, XLP typically manifests in early childhood and is characterized by intense burning and itch of sun-exposed skin within minutes of sun exposure [5]. These symptoms can be accompanied by erythema and swelling and often affect the dorsal hands [7]. Over time, repeated acute photosensitive episodes may result in lichenification and loss of nail lunulae [7, 32]. X-linked protoporphyria is also associated with systemic complications, including anemia and dysregulated iron metabolism, with anemia reported in 30% of male patients with XLP and 75% of female patients with XLP [18]. Additionally, patients with XLP are at increased risk of protoporphyric liver disease, though this risk may be lower than in EPP [30]. One study found that 22.1% of patients with EPP had gallstones, while 40% of male patients with XLP and 33.3% of female patients with XLP had gallstones [18].

3.2.4 Diagnosis

Diagnosis of XLP relies on markedly elevated total erythrocyte protoporphyrins [19]. However, XLP is distinguished by a lower metal-free proportion that is typically 50–85%, compared with 85–100% in EPP [12, 19]. Genetic testing of the ALAS2 gene helps confirm XLP, identifying asymptomatic or variably symptomatic female carriers and distinguishing XLP from EPP [19, 28].

3.2.5 Treatment and Management

Treatment and management of XLP are similar to EPP, with a focus on reducing phototoxic and hepatic injury.

3.3 Congenital Erythropoietic Porphyria (CEP)3.3.1 Pathobiology

Congenital erythropoietic porphyria, also known as Günther disease, is a rare blistering cutaneous porphyria caused by a deficiency of UROS [7]. This is the fourth enzyme in the heme biosynthesis pathway, which converts hydroxymethylbilane to uroporphyrinogen III [11]. When UROS activity is reduced in CEP, cyclization of hydroxymethylbilane leads to uroporphyrinogen I accumulation, resulting in coproporphyrinogen I following the decarboxylation of uroporphyrinogen [34, 35]. These non-physiologic isomers accumulate in erythroid precursors, undergo auto-oxidation to coproporphyrin I and uroporphyrin I, and deposit in erythrocytes and skin [35, 36]. These porphyrins are highly photoactive, generating reactive oxygen species that damage tissues and vascular structures, producing the characteristic blistering and skin fragility in CEP [7].

3.3.2 Inheritance and Epidemiology

Congenital erythropoietic porphyria is inherited in an autosomal recessive pattern with two pathogenic variants of UROS [37]. Previous studies have also reported a GATA1 pathogenic variant, which alters the binding of GATA1 to UROS, on the X chromosome in one patient [38]. Congenital erythropoietic porphyria is an extremely rare disorder, with approximately 220 cases reported worldwide [35].

3.3.3 Clinical Features

The phenotypic spectrum of CEP ranges from non-immune hydrops fetalis to late-onset disease manifesting as mild photosensitivity [37, 39]. Congenital erythropoietic porphyria typically presents at birth or in infancy with blistering and skin fragility of sun-exposed skin, which can lead to infection, scarring, hypertrichosis, and photomutilation of the digits and face [7,