Congenital erythropoietic porphyria in two siblings
Andréia Jacobo¹, Hiram Larangeira de Almeida Jr², and Valéria Magalhães Jorge¹
Dermatology Online Journal 11 (3):

Introduction

Congenital erythropoietic porphyria (CEP) is an autosomal recessive disease in which the gene that codes for the uroporphyrinogin-III synthetase (URO-III s) (found in chromosome 10) is mutated [1, 2, 3]. The C73R mutation is the most frequent, in which cysteine is substituted by arginine, and, in this way, damages the disulphate bridges, which influences the secondary structure of the enzyme. Other deletions and insertions have also been described.

The URO-III s is one of the enzymes responsible for the synthesis of heme in erythrocytes. Physiologically, URO-III s converts hydroxymetilbilane into uroporphyrinogene III. In URO-III s deficiency almost 85 percent of hydroxymetilbilane spontaneously condenses into isomer I or biologically inactive uroporphyrin I (UROI), while 15 percent condenses into isomer III (uroporphynogene III) [4]. URO I mainly accumulates in the bones, erythrocytes, skin and teeth and is accompanied by the excretion of large quantities of porphyrins in the urine and feces. Uroporphyrins and other metabolic deposits in the skin produce oxidative damage when exposure to light occurs.

Case reports

Case 1

A 43-year-old single male farmer had dark skin, hypertrichosis, and dark urine present from birth. At age 8 his teeth were noted to change in color and blisters and vesicles appeared on sun-exposed areas. The blisters became ulcers that healed with difficulty. Gradually, the areas that developed repeated blisters became sclerotic. The maternal grandparents were first cousins. He has nine siblings, one of whom presented the same skin condition (Case 2). Skin examination revealed ulcers, hyperkeratosis, hypopigmentation, and fibrosis in sun-exposed skin (Fig. 1), especially on the face, scalp, ears, arms, and hands (which were severely mutilated) (Fig. 2).

Figure 1	Figure 2
Figure 1. Case 1: Sclerodermiform changes and hyperkeratosis in sun-exposed areas.
Figure 2. Case 1: Severe sclerodermiform mutilation and ulcer formation of the hand.

Figure 3
Case 1: Light microscopy with fibrosis and absence of annexes(HE 200x), inset shows amorphous material in the papilary dermis (PAS 400x).

Blood cell count showed 5.5 million erythrocytes /mm³, hemoglobin 18.9 g/ml, hematocrit 50 percent, MCH 30 mg, MCHC 34 percent, MCV 90 micra³. The leucogram and platelets were normal. The hepatic enzymes were slightly elevated, OGT 47 u/ml (normal range 7-27), PGT 39 u/ml (4-26) and gamma-GT 15 U/L.

The 24-hour urine porphyrin analysis revealed coproporphyrins of 382.2 mcg/g of creatinine (normal being less than 100 mcg/g of creatinine - colormetric method) and positive uroporphyrins (fluorescence method). The analysis of porphyrins in the erythrocytes showed a level of 98.6 mcg/100ml (reference value less than 40mcg/100ml using the hematofluorometric method).

Light microscopy of a fragment of skin from the forearm showed epidermal atrophy with prominent dermal fibrosis and the absence of cutaneous adenexal structures. PAS staining showed the presence of an amorphous substance (Fig. 3).

Case 2

A 29-year-old single male farmer had dark skin and dark urine present since birth. He also had a notable excess of body hair, especially on the face, since puberty. Vesicles and blisters occurred after exposure to the sun.

Figure 4	Figure 5
Figure 4. Case 2: Fibrosis of exposed skin and microstomia.
Figure 5. Case 2: Hypertricosis and initial acrosclerosis (so-called werewolf hand).

Skin examination showed areas of hyperpigmentation and fibrosis of the face with retraction of the perioral region. He also had fibrotic changes of the ears and nose (Fig. 4). The hands showed intense hypertrichosis and shortening of the distal phalanx (so-called werewolf hands) (Fig. 5). The teeth were stained a chestnut color. Blood tests revealed the following: 5.76 million erythrocytes /mm³, hemoglobin 20.3 g/ml, hematocrit 52 percent. HCM 31mg, MCHC 34mg, MCV 91 micra³, leucogram and platelets were normal, OGT 46 u/ml (normal range 7 - 27), PGT 80 u/ml (4 - 26), gamma-GT 39 u/l (6-25).

Figure 6
Case 2 : Light microscopy with slight fibrosis (HE 200 x), inset shows amorphous material around the sweat gland (PAS 400x).

Quantitative 24-hour urine porphyrins revealed coproporphyrins at a creatinine level of 718.4 mcg/g (normal level less than 100 mcg/g using the colormetric system) and positive uroporphyrins using the fluorescence method. The search for porphyrins in the erythrocytes showed a level of 124.3 mcg/100ml (reference value less than 40 mcg/100ml using the hematofluorometric method).

Light microscopy of a skin fragment taken from the lower arm showed dermal fibrosis with deposits of periadenexal, dermal, and perivascular hyaline material (Fig. 6).

Discussion

In CEP urinary porphyrins may increase from 100 to 1,000 times, predominantly in the more carboxylated form, URO I, which is water soluble.

Moreover, the excretion of urinary uroporphyrin III and coproporphyrin III is increased. The excretion of precursors of delta aminolevulinic acid and porphobilinogen are normal in CEP [5].

Photosensitivity frequently occurs in the first few days of life and is especially induced by light at a frequency of approximately 405 nm. During the course of the illness there occurs intense fragility of the skin that produces ulcers followed by the mutilation involving fingers, hands, face, and especially the nose, ears, lips, cheeks, and forehead. The fingers and fingernails are also deformed [6]. Hypertrichosis and erythrodontia, as in case 2, are also characteristic [7].

Ocular involvement with blepharitis, scarring ectropion, conjunctivitis and the complete loss of eyelashes and eyebrows is common. Corneal scarring may also lead to blindness. Scleromalacia, diminished corneal sensitivity, pterion, atrophy of the optic nerve and retinal haemorages may also occur. In long-term cases, severe osteolysis accompanied by mutilation is found, associated with severe contraction and atrophy of the fingers, similar to that which occurs in scleroderma and resulting in acromicria, as occurred with the severe mutilation of the hands in Case 1.

The main histopathological changes observed in CEP are subepidermal blisters, similar to porphyria cutanea tarda, with an increase in scarring and hyalinization of the conjunctive tissue as was seen in the two cases under study here. The only available prophylactic measure for CEP is total abstinence from exposure to the sun [8]. Sun avoidance is also important in order to prevent cutaneous neoplasms, one of the complications of CEP [9].

Transfusion of erythrocytes may be effective in dealing with hemolytic anemia by inducing polycythemia and consequently a negative feedback in the biosysnthesis of porphyrins in the bone marrow. Less severely affected patients may be successfully treated on a long-term basis with transfusion therapy. The benefit of blood transfusion decreases during puberty when hormonal changes increase the biosynthesis of heme [8].

Bone marrow transplant is an effective therapeutic option for CEP as this substitutes the erythroblasts of the medulla, thereby correcting the erythrocyte defect. This treatment also normalizes the activity of URO III synthetase, thereby reducing porphyrin levels with a resulting lessening of photosensitivity and cutaneous fragility; normal erythropoiesis is re-established [10].

Although CEP is quite rare, other familial cases have been described [11, 12, 13], including one other from Brazil [14].

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