August 2023 – Biochemical Genetics

A 31-month-old girl presented with cutaneous ulcerations on her face, hands, and arms. She has hepatosplenomegaly and slight elevations in liver function tests. The care team suspects porphyria and orders biochemical and molecular testing. Blood, urine, and fecal samples were tested for any abnormal accumulation of porphyrins and intermediates of the porphyrin biosynthesis pathway. Erythrocyte uroporphyrinogen decarboxylase (UROD) activity was markedly reduced by 95% when compared to normal individuals. Urine and fecal porphyrin analysis detected abnormally high excretion of uroporphyrinogen III (Figure 1). The excretion of Coproporphyrinogen III precursors (heptacarboxyl porphyrin, hexacarboxylporphyrin, and pentacarboxyporphyrin) were markedly elevated in urine (Figure 1A; this test does not separate isomer I to isomer III species). In addition, the excretion of isocoproporphyrins was detected in feces (Figure 1B). The excretions of aminolevulinic acid and porphobilinogen were normal. Fractionation of protoporphyrins in whole blood showed an elevation of zinc-associated protoporphyrins (Figure 2). Molecular testing using a 10-gene porphyria panel identified two pathogenic variants in UROD.

Figure 1: Patient urine (1A) and fecal (1B) porphyrin analysis and quantification by liquid chromatography. 
Figure 2: Liquid chromatography fractionation of patient whole blood showing elevations of free and zinc-associated protoporphyrin (mcg/dL, in red).  Normal free protoporphyrin is <20 mcg/dL and normal zinc-associated protoporphyrin is < 60 mcg/dL.

Based on these findings, what is the possible diagnosis of the patient? 

  • Familial porphyria cutanea tarda
  • Congenital erythropoietic porphyria
  • Hepatoerythropoietic porphyria
  • Erythropoietic protoporphyria

The correct answer is ...

Hepatoerythropoietic porphyria.

Hepatoerythropoietic porphyria (HEP) is an extremely rare, autosomal recessive genetic disorder characterized by deficiency of the enzyme UROD. Fewer than 100 cases have been reported. Most affected individuals have a profound deficiency of this enzyme, and the onset of the disorder is usually during infancy or early childhood. Symptoms and severity can vary, but patients generally experience severe cutaneous photosensitivity and fragile skin. Affected skin can become discolored and prone to bacterial infection. Hypertrichosis on sun-exposed skin and erythrodontia are common. Bone fragility and hemolytic anemia often result. Abnormalities in liver function may also occur.1 

Pathogenic variants in UROD can cause two porphyria conditions: familial porphyria cutanea tarda (PCT type II) and hepatoerythropoietic porphyria (HEP).2 A significant biochemical and clinical overlap exists between the two conditions. Reduced UROD activity in all tissues leads to the accumulation of uroporphyrinogen III and precursors of coproporphyrinogen III synthesis (heptacarboxylporphyrin, hexacarboxylporphyrin, and pentacarboxyporphyrin). 

Although the UROD activity is low in both PCT type II and HEP, a UROD activity of <10% is typically seen in HEP patients.3 This contrasts with PCT type II patients who have UROD activity of approximately 50%. Secondly, PCT is usually a late-onset disease with symptoms first manifesting in the early 30s. The patient presented here has an early onset of disease, which is characteristic of HEP. Additionally, PCT type II is inherited in an autosomal dominant manner while HEP is inherited as an autosomal recessive trait. Increased isocoproporphyrins in feces are characteristic of both PCT type II and HEP.4 In contrast to PCT, erythrocyte zinc-associated protoporphyrin is increased in HEP. 

Porphyria cutanea tarda type II (vs hepatoerythropoietic porphyria)

Porphyria cutanea tarda is the most common porphyria. Although porphyria cutanea tarda is a late-onset condition, early-onset cases have been reported. Three types of PCT exist: type 1 (acquired or sporadic, 80%); PCT, type 2 (familial PCT, 20%); and type 3 (no pathogenic variants in UROD, cause unknown).5 

Congenital erythropoietic porphyria 

Congenital erythropoietic porphyria (CEP) presents in infancy and is the rarest porphyria. CEP is an autosomal recessive porphyria caused by pathogenic variants in the uroporphyrinogen III synthase (UROS). Patients present with cutaneous photosensitivity (redness, blistering, thickening) and increased vulnerability to skin infection. Erythrodontia is common. Vomiting, abdominal pain, and constipation may occur during attacks. Hepatic and hematological involvement has been reported.1 While CEP and HEP share some common clinical features, the biochemical phenotypes are different. Biochemically, uroporphyrinogen I and coproporphyrinogen I accumulate in the blood. Measurement of these analytes in fecal, blood, and urine samples can establish a diagnosis for CEP. 

Erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is caused by low ferrochelatase activity, the last enzyme in the heme biosynthetic pathway. While both EPP and HEP are classified as cutaneous porphyrias, the clinical and biochemical phenotypes are different. EPP patients have an immediate, painful reaction to sunlight while HEP manifests with severe, bullous sun sensitivity.6 Contrary to elevated zinc-associated protoporphyrin observed in HEP patients, EPP patients show excess accumulation of metal-free protoporphyrin in red blood cells, plasma, and fecal specimens. Additionally, the urine porphyrin profile is normal in EPP patients. 


There is no cure for HEP. Avoidance of exposure to triggering agents and management of symptoms remains the key strategy for the improvement of patient outcomes. 


  1. Cheryl B. Bayart and Heather A. Brandling-Bennett. Congenital and Hereditary Disorders of the Skin. 2018:1475-1494.e1.
  2. Weiss Y, et al. Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations. Mol Genet Metab. 2019. 128:363-366.
  3. Amy S. Paller and Anthony J. Mancini. 19 - Photosensitivity and Photoreactions. Hurwitz Clinical Pediatric Dermatology (Fourth Edition), 2011:436-453,.
  4. Eulalia Baselga and Antonio Torrelo, Chapter 19 - Inflammatory and Purpuric Eruptions. 2008:311-342.
  5. Aarsand AK, Boman H, Sandberg S. Familial and sporadic porphyria cutanea tarda: characterization and diagnostic strategies. Clin Chem. 2009:10(1373).
  6. Mario Lecha, Hervé Puy, Jean-Charles Deybach. Erythropoietic protoporphyria. Orphanet Journal of Rare Diseases. 2009(4).

Gerald Dayebgadoh, Ph.D.

Fellow, Clinical Biochemical Genetics
Mayo Clinic

Tricia Hall, Ph.D.

Senior Associate Consultant, Laboratory Genetics and Genomics
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

MCL Education (@mmledu)

MCL Education

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