Gunther disease

Signs and symptoms

Severe cutaneous sensitivity is present in most cases, though expressivity varies with the mutation. Exposure to long-wave ultraviolet light causes thickened skin and vesicles prone to rupture and infection, which along with bone resorption can lead to disfigurement of sun-exposed areas. Hemolytic anemia is common, though a lack of hemolysis is possible. Porphyrins accumulate in bones and teeth, causing erythrodontia.

Attacks may include abdominal pain, vomiting, and constipation. Photomutilation and transfusion-dependent anemia are frequent complications; liver disease occurs in some cases. Early childhood-onset hematologic manifestations indicate a poor prognosis.

Causes

Gunther disease is caused by mutations in the UROS gene, located on human chromosome 10q25.2-q26.3, which encodes uroporphyrinogen III synthase. The disorder is inherited in an autosomal recessive manner, requiring two defective gene copies. A homozygous mutation leads to a defect in uroporphyrinogen III synthase and uroporphyrinogen cosynthase. Normally, this enzyme produces isomer III porphyrinogen for heme formation; when deficient, isomer I porphyrinogen is made, which oxidizes and gives a reddish tint to the skin.

Diagnosis

Diagnosis of congenital erythropoietic porphyria requires excluding other porphyrias such as hepatoerythropoietic porphyria, rare homozygous variants of variegate porphyria, hereditary coproporphyria, and SAVI. Mild variants may resemble porphyria cutanea tarda. Four steps establish diagnosis: thorough history and physical exam focusing on sun-exposed skin; biochemical measurement of porphyrins and precursors in urine, feces, and blood; specialized labs measuring enzyme activity or DNA analysis; and markedly decreased uroporphyrinogen III synthase activity.

Urine aminolavulanic acid and porphobilinogen are typically normal, while uroporphyrin and coproporphyrin are elevated in urine. Fecal protoporphyrin is mildly elevated. Red blood cells show elevated uroporphyrin, coproporphyrin, and protoporphyrin. Plasma analysis shows elevated uroporphyrin and coproporphyrin.

Diagnostic clues include photosensitivity, blistering, scarring, erythrodontia, hemolytic anemia, and red or violet staining of diapers.

Treatment

Limiting or eliminating sun exposure is crucial. Sunscreens containing zinc oxide and titanium dioxide provide protection as light-reflective agents, but physical barriers are needed to block ultraviolet and visible light. Protective clothing and plastic films on car windows and homes help filter harmful wavelengths. Incandescent bulbs should replace fluorescent lamps to avoid porphyrin-exciting wavelengths.

Oral beta-carotene, activated charcoal, and cholestyramine have been used to interrupt porphyrin reabsorption but require extremely large doses and are not beneficial. Erythrocyte transfusions can lower erythropoiesis and circulating porphyrin levels, but chronic transfusions cause severe complications.

Topical lubrication helps with dry eye symptoms and visual function. Bone marrow transplantation has been reported successful in numerous studies, though long-term effects are not yet documented; it is not relevant for patients with life-threatening infectious complications. Stem cell transplantation has been successful in a limited number of participants.