Congenital Erythropoietic Porphyria (CEP)

Pathophysiology and Cellular Genetics

UROS Deficiency and a Diverted Metabolic Pathway

In normal heme synthesis, UROS converts hydroxymethylbilane (HMB) into uroporphyrinogen III, the useful biological precursor.

• Mutations in UROS: patients with CEP carry two mutated alleles of the UROS gene (on chromosome 10q26.2). UROS activity is usually below 10% of normal.
• Accumulation of type I isomers: without enough UROS, HMB spontaneously cyclizes into uroporphyrinogen I, which is then converted to coproporphyrinogen I. Neither type I isomer can proceed to heme, so they accumulate and oxidize into free uroporphyrin I and coproporphyrin I, which are highly phototoxic.
• Buildup in the bone marrow (erythroid precursors): unlike PCT and HEP, where porphyrins accumulate mainly in the liver, the main source of porphyrins in CEP is the red cell precursors in the bone marrow.

Phototoxicity and Damage to Bones and Teeth

• Soret absorption band (400–410 nm): uroporphyrin I and coproporphyrin I dissolve in the blood and settle in the basement membrane, dermal vessel walls, bone and tooth enamel. When exposed to visible blue-violet light, they generate large amounts of toxic reactive oxygen species (ROS) that kill cells.
• Red teeth (erythrodontia): porphyrins bind tightly to calcium phosphate in developing bones and teeth. The teeth of children with CEP are reddish-brown or grayish and glow bright red under a Wood's lamp (365 nm).
• Hemolysis and the bone marrow response: porphyrin-laden red cells rupture easily as they pass through light-exposed skin, causing chronic hemolytic anemia. The marrow responds by producing many times more red cells, which in turn generates even more toxic porphyrins, creating a dangerous vicious cycle.

Characteristic Clinical Features of Günther Disease (CEP)

Symptoms of CEP usually appear very early; the disease may even be detected in the womb (hydrops fetalis) or within days of birth.

Skin and Musculoskeletal Features

• Bright red urine in the diaper: often the first sign parents notice. The urine is dark red, blood-red or wine-colored because of the massive amounts of uroporphyrin I being excreted.
• Blisters and skin necrosis: as soon as the skin is exposed to natural sunlight or to neonatal jaundice phototherapy lamps, large blisters form and break down into deep, necrotic ulcers.
• Severe mutilation:
  • Face: progressive scarring disfigures the whole face, with loss of the ear rims and nasal cartilage, eyelid retraction (ectropion) and lip contraction that exposes the red teeth.
  • Hands: contracting scars stiffen the joints, and resorption of the finger bones (dactylolysis) leads to loss of finger and toe segments, leaving claw-like hands.
• Dense hair growth (hypertrichosis): dark, fine hair grows thickly on the face, forehead, back and limbs, the body's natural attempt to shield the skin from light.

Hematologic and Systemic Features

• Severe hemolytic anemia: children are often pale, grow poorly and become fully dependent on blood transfusions.
• Massive splenomegaly: the spleen enlarges from constantly destroying abnormal porphyrin-laden red cells, leading to hypersplenism (low white cells and platelets as well).
• Osteoporosis and bone deformity: porphyrin deposits in bone combined with excessive marrow expansion thin the bone cortex, making spontaneous fractures very common.

Biochemical and Genetic Diagnosis at Haute-Derma

Porphyrin Biochemistry

• Urine: uroporphyrin I and coproporphyrin I are raised hundreds of times above normal, with uroporphyrin I far exceeding uroporphyrin III.
• Red cells and plasma: large amounts of free uroporphyrin I accumulate in red blood cells.
• Stool: coproporphyrin I is present at very high levels.

Enzyme Assay and Molecular Testing

• UROS enzyme activity: measured in red cells or fibroblasts, it is below 10% of normal.
• Genetic testing for UROS: sequencing detects common mutations such as the C73R point mutation (p.Cys73Arg), a frequent change that leaves the enzyme severely nonfunctional.

Treatment and Clinical Management at Haute-Derma

CEP is a complex disease whose treatment requires a multidisciplinary team of dermatologists, hematologists, pediatricians and clinical geneticists.

Maximal Light Protection and Skin Care

• Avoiding visible light (Soret band, 400–410 nm):
  • Keep the child out of direct sunlight entirely.
  • Fit blue-violet light-blocking film to the windows at home and in the car.
  • Apply a thick layer of specialized mineral sunscreen containing iron oxides plus zinc oxide to exposed skin.
• Wound care and infection prevention:
  • Apply a gentle antiseptic and cover blisters with non-adherent petrolatum gauze.
  • Use antibiotic cream promptly to prevent cellulitis and osteonecrosis of the fingers.

Marrow Suppression and Hematologic Support

• Regular red cell transfusions: keeping hemoglobin high sends a negative feedback signal that suppresses the marrow's own production of porphyrin-laden red cells.
• Iron chelation: repeated transfusions risk iron overload, leading to liver cirrhosis and heart failure. An iron chelator such as deferasirox or deferoxamine is essential to keep ferritin under control.
• Splenectomy: considered for severe hypersplenism; it prolongs the survival of transfused red cells and reduces how often transfusions are needed.

Curative Treatment: Hematopoietic Stem Cell Transplantation (HSCT)

• The only cure: allogeneic HSCT from an HLA-matched donor is currently the only treatment that can cure Günther disease at its root.
• Outcome: once the donor stem cells engraft, the new marrow produces red cells with normal UROS. Hemolytic anemia resolves completely, blood porphyrin levels return to normal and skin damage stops progressing.
• Timing: transplantation should be done as early as possible, before irreversible scarring of the skin and bone deformity set in.