Background and Clinical Significance: Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive porphyria caused by a deficiency of uroporphyrinogen III synthase, leading to the accumulation of phototoxic type I porphyrins. CEP classically presents in infancy with severe photosensitivity, blistering, scarring, and hemolytic anemia; however, significant phenotypic variability has increasingly been recognized. Case Presentation: We report a 32-year-old woman diagnosed with CEP in early infancy who demonstrated persistently and profoundly elevated erythrocyte porphyrin levels over more than a decade, yet who followed a relatively non-mutilating clinical course. Genetic testing identified a low-penetrance intronic UROS variant typically associated with erythropoietic protoporphyria, underscoring diagnostic challenges and genotype-phenotype discordance. The patient experienced marked improvement in photosensitivity and burning pain after initiation of afamelanotide, without the need for transfusion therapy or stem cell transplantation. Conclusions: This case highlights the heterogeneity of CEP, the importance of long-term biochemical follow up, and the potential role of afamelanotide in improving quality of life for selected patients with CEP.

Erythropoietic protoporphyria (EPP) is an autosomal recessive disorder of the heme biosynthesis pathway caused by pathogenic variants in FECH gene resulting in a decreased activity of ferrochelatase. Liver involvement is observed in 5%-20% of patients harbouring loss-of-function FECH variants and its manifestations are heterogeneous, ranging from mildly elevated liver transaminases, cholelithiasis to severe acute cholestatic hepatitis/liver failure. This paper presents the case of a Polish infant with EPP associated with two novel missense FECH variants accompanied by other congenital anomalies, namely atrial septal defect and renal hypodysplasia. Progressive cholestatic liver disease (with subsequent congestive heart failure) was observed in the course of EPP. Erytropoietic protoporphyria should be considered in patients with hepatosplenomegaly and cholestasis accompanied by skin damage. The natural history of liver disease in the course of EPP could be determined by other factors, like the co-existence of congenital anomalies.

Erythropoietic protoporphyria (EPP) is a rare autosomal recessive disorder caused by mutations in the FECH gene, leading to ferrochelatase deficiency and the accumulation of protoporphyrin in various organs. EPP patients with liver damage have atypical histopathological manifestations, which pose challenges for pathological diagnosis. We report a 29-year-old male with recurrent abdominal pain and scleral jaundice. Initial liver dysfunction suggested autoimmune hepatitis, but liver biopsy revealed dense brownish granular deposits with red birefringence under polarized light, characteristic of EPP. Genetic testing identified a new mutation site (c.804 + 1del), which may be related to the disease. Additionally, the patient also has Gilbert's syndrome. This case highlights the diagnostic challenges of EPP and the importance of integrating clinical history, histopathology, and genetic testing. Polarized light microscopy is crucial for identifying the characteristic features of EPP. Early genetic testing can guide timely diagnosis and treatment, contributing to the understanding of this rare condition.

Afamelanotide 16 mg (SCENESSE) is the first approved treatment for erythropoietic protoporphyria (EPP). EPP is a rare autosomal recessive inherited disorder of the haem biosynthesis pathway, where patients experience severe and debilitating acute phototoxicity. It affects at least one in 140,000 of the European population. A postauthorisation safety study (PASS) and a disease registry were imposed as conditions of the European marketing authorisation. Evaluate the short- and long-term safety and clinical effectiveness of afamelanotide 16 mg in EPP patients enrolled in the PASS in Germany. The PASS (EUPAS13004) is an ongoing observational study collecting safety and effectiveness variables from treated and untreated EPP patients in the European EPP Disease Registry. Patients (n = 200, none untreated) received afamelanotide according to the summary of product characteristics. Treatment-emergent adverse events were collected as safety variables. Clinical effectiveness was assessed with the EPP-QoL tool and through treatment continuity. The short- and long-term safety and benefit-risk profile of afamelanotide under real-world conditions is consistent with the positive safety profile seen in clinical trials. EPP patients reported a significant increase in QoL compared with baseline values (p < 0.0001) and 91.0% of patients who started treatment continue being treated. The safety profile of afamelanotide in patients over 70 years of age is consistent with the overall patient population. Afamelanotide treatment was highly effective and associated with a higher QoL in EPP patients. The study shows a positive safety profile of afamelanotide, with the treatment providing an ongoing clinical benefit.

Xeroderma pigmentosum is a rare autosomal recessive genodermatoses characterized by a deficiency in nucleotide excision repair. Erythropoietic protoporphyria is a rare inherited metabolic disease caused by the perturbation of heme. Xeroderma pigmentosum-erythropoietic protoporphyria is exceedingly rare. Hereby, we firstly report a young Chinese patient of xeroderma pigmentosum Group A with erythropoietic protoporphyria carrying an XPA Met214AsnfsTer7 frameshift mutation and a homozygous splicing mutation, c.315-48T>C, in the proband's intron3 of FECH.