Congenital Erythropoietic Porphyria - Heme, Light, and Blistering

What Is Congenital Erythropoietic Porphyria?

Congenital erythropoietic porphyria (CEP), or Gunther disease, is an extremely rare metabolic disorder caused due to genetic mutations. Heme biosynthesis is an eight-step process; a genetic mutation disrupts this pathway, causing skin blistering from light exposure. Porphyrin accumulation turns out to be the essential etiology of CEP.

Who Is Susceptible to Congenital Erythropoietic Porphyria?

American Porphyria Foundation maintains a porphyria registry to estimate the prevalence of CEP. Worldwide, a few hundred cases have been reported to date. Due to a lack of prevalence estimates, the predilection or a lack thereof has not been established in other parameters. No racial or gender predilection has been observed. As per the name, the condition is typically seen in infants and young children, with several adult-onset cases being reported.

What Is the Cause of Congenital Erythropoietic Porphyria?

CEP is an autosomal recessive disorder caused due to mutation in chromosome 10. UROS gene encoded uroporphyrinogen III synthase enzyme. Due to its recessive inheritance nature, both parents have to contribute the mutated gene in order to have an affected offspring. A dysfunctional UROS gene produces a deficient uroporphyrinogen III synthase enzyme, which shifts the heme synthesis pathway from isomer III porphyrinogen production and results in the overproduction of isomer I porphyrinogen. This accumulated compound cannot be transformed into heme and gets oxidized to corresponding porphyrins, which are water-soluble photosensitive compounds giving a reddish hue. C73R mutation, which is responsible for more than 20 percent of CEP cases, shows the most severe deficiency of the UROS enzyme. C73R mutation leads to premature protein degradation of the UROS enzyme by interfering with protein stability.

The GATA family of genes is a group of transcription factors involved in human hematopoiesis. Mutations in the GATA1 gene, an X-linked transcription factor, are also reported to be involved with erythropoietic porphyria.

The porphyrins are released from matured erythrocytes into the blood plasma and are filtered out by the kidney, giving out port-wine color urine. Accumulation of excess porphyrin or uroporphyrinogen I in the skin, in the presence of 404-nanometer wavelength of light, free radicals are formed, leading to photodermatitis. This compound and light interaction caused photooxidative damage to the skin, presenting as mechanical fragility, blistering, and severe scarring. Uroporphyrinogen shows fluoresces under ultraviolet light, presenting a reddish discoloration of the teeth and sclera under Wood light. Even the urine glows fluoresce under ultraviolet light.

The resulting hemolytic anemia, following erythrocyte death, may also lead to hypersplenism (overactive spleen). Some cases also show hypertrophy of the bone marrow which can lead to bone fragility and pathologic fractures. Skeletal manifestations can lead to acral osteolysis (bone resorption of the distal phalanges) and onycholysis (separation of the nail from nailbed), staining of teeth and bone. Additionally, ocular damage may also be seen. Owning to the photoactive nature of the compounds, bright pink fluorescence can be seen due to the disposition in urine, teeth, and bone under Wood light.

What Are the Clinical Features of Congenital Erythropoietic Porphyria?

Cutaneous Manifestations:

• Photosensitive skin.

• Vesicles.

• Bullae.

• Increased skin fragility.

• Skin erosions.

• Hypertrichosis (excessive hair growth).

• Scleroderma-like skin (hardening and tightening of the skin).

• Hyperpigmentation of skin.

• Papules around the mouth (hamartomas).

Ocular Manifestations:

• Blepharitis (eyelid inflammation).

• Cicatricial ectropion (short anterior lamella of the eye lid).

• Conjunctivitis.

• Lagophthalmos (incomplete eyelid closure).

• Interpalpebral fissures anomalies.

• Pink fluorescence of sclera under Wood light.

• Scleral necrosis.

• Bilateral corneal scarring.

• Chronic ulcerative keratitis.

• Scleromalacia (autoimmune damage to the blood vessels).

Skeletal Manifestations:

• Severe bone loss.

• Skeletal contractures.

• Skeletal deformities.

• Osteopenia (loss of bone density).

• Acro osteolysis (one resorption of the distal phalanges).

• Pathologic fractures.

• Bony fragility.

• Orange-red fluorescence of the bones.

• Mutilation and disfigurement of face, hands, and fingers.

• Short stature.

• Osteoporosis (weak and brittle bones).

Other Systemic Manifestations:

• Hemolytic anemia (increased hemolysis leading to blood shortage).

• Splenomegaly (increased size of the spleen).

• Reddish teeth under Wood light (erythrodontia).

• Pink-stained urine under Wood light.

How to Diagnose Congenital Erythropoietic Porphyria?

Usually, accidentally noticing the staining of the teeth and urine can be the reason for a clinical appointment. The doctor orders several tests in order to extrapolate the accurate diagnosis.

Laboratory Studies:

• 100 to 1000 times increase in urinary porphyrin concentrations (mostly uroporphyrin I).

• Elevated levels of uroporphyrin III and coproporphyrin III (but less than uroporphyrin I).

• Elevated zinc protoporphyrin.

• Elevated levels of uroporphyrin I in the erythrocyte.

• Coproporphyrin accumulation as fecal porphyrin.

Complete Blood Count:

• Excessive uroporphyrin in red blood cells.

• Hemolytic anemia.

Ultrasound Reports:

• Hepatomegaly.

• Splenomegaly.

Histopathological Studies:

• Subepidermal blister.

• Superficial perivascular lymphocytic infiltrate.

• Thickened, hyalinized wall of blood vessels.

• Blood vessels are PAS positive (periodic acid-Schiff), meaning that they have diastase-resistant glycoproteins.

• Festoons in the blister cavity.

• Caterpillar bodies (linear eosinophils) at the bullae roofs.

Other Test:

Fluorescence microscopy of blood and bone marrow shows red porphyrin fluorescence in intact and blood cell precursors under violet or blue illumination against a dark field. Brilliant fluorescence of nuclei within the blood precursor cells is characteristic of erythropoietic porphyria. DIF (direct immunofluorescence tests) show linear C3 (complement component 3) and IgG (immunoglobulin G) antibodies around the superficial blood vessels and along the dermo-epidermal junctions. Diagnostic confirmation can be obtained by measuring the UROS enzyme activity or by identifying the mutated gene in the genome by molecular genetic analysis.

How to Treat Congenital Erythropoietic Porphyria?

Owning to its genetic onset and lack of treatment urges clinicians to recommend stringent protective measures against aggravation or onset of symptoms.

Some of the recommendations of the management protocols are:

• Use of topical sunscreens with Zinc Oxide or Titanium Dioxide.

• Physical measures like sun-protective clothing and polarized sunglasses.

• Sun-protective films over home and automobile windows.

• Use of incandescent light instead of fluorescent lamps.

• Oral Beta-Carotene supplements.

• Vitamin D supplements.

• Low-dose Hydroxychloroquine to increase porphyrin excretion.

• Afamelanotide (injectable subcutaneous implant used to mitigate phototoxicity).

• Activated charcoal and Cholestyramine to interrupt and prevent the reabsorption of porphyrins.

• Erythrocyte transfusion reduces erythropoiesis, thus lowering porphyrin levels in the circulating blood volume.

• Oral Alpha-Tocopherol and Ascorbic Acid that reduces reactive oxygen radicals can reduce photooxidative damage to skin and blood cells.

• Topical ocular lubrication and antibiotics.

• Bone marrow transplant.

• Stem cell transplant.

• Splenectomy (surgical removal of the spleen).

What Is the Differential Diagnosis of Congenital Erythropoietic Porphyria?

• Porphyria cutanea tarda (skin disease similar to CEP etiology).

• Protoporphyria (inherited porphyria causing protoporphyrin accumulation).

• Pseudoporphyria (bullae formation without porphyrin metabolism dysfunction).

• Variegate porphyria (deficient function of the enzyme protoporphyrinogen oxidase).

• Xeroderma pigmentosum (extreme sensitivity to ultraviolet (UV) rays from sunlight).

Conclusion:

Congenital erythropoietic porphyria is a rare disease and requires stringent management protocols. American Porphyria Foundation and similar establishments in various other countries are conducting several studies and research with the hope of improving the quality of life of the patients. With a diagnosis in hand, the patient may consult their nearest porphyria center for tailored care and counseling. Pertaining to the manifestation of symptoms in various systems, a multi-department approach has to be followed for the infant to grow into a normal childhood and adult thereafter.