Dark Age Vampires or Our Poor Patients

Abstract

A 10-year-old child, born of first degree consanguineous marriage, presented with photosensitivity and recurrent blistering on exposed areas that used to heal with scarring along with passing red color urine since the age of 1 year. Mental and physical development was normal. Family history for this disease was negative. There was no history of acute neurological attacks. On examination there were areas of hyperpigmentation, hypertrichosis, and atrophic scars on the face with retraction of the perioral region. He also had fibrotic changes of the ears and nose [Figures 1 and 2]. The hands showed intense hypertrichosis and shortening of the distal phalanx (so-called werewolf hands) [Figure 3]. The teeth were chestnut color stained and revealed a pinkish red fluorescence under Wood's lamp. Severe anemia, congestive cardiac failure, and massive splenomegaly were present. Figure 1 Hyperpigmentation, hypertrichosis, sclerodermiform changes and hyperkeratosis in sun-exposed areas Figure 2 Fibrosis of exposed skin and microstomia Figure 3 Hypertrichosis and initial acrosclerosis (so-called werewolf hand) Investigations revealed severe anemia (Hb 2.0 g/dL) with a normal urine porphobilinogen (PBG). On screening with a spectrophotometer, urinary total porphyrin was 1064 nmol/mmol of creatinine (normal < 35 nmol/mmol). Twenty-four-hour urinary levels of uroporphyrin and coproporphyrin were raised. The erythrocytic porphyrins showed a level of 1132 μg/100 mL (reference value less than 40 μg/100 mL using the hematofluorometric method). Patient was treated symptomatically. Question What is the diagnosis? What is the pathology behind the condition? What are the mimickers and how can they be differentiated? What should be the management strategy for the condition? Answer 1 Congenital erythropoietic porphyria (Gunther disease). The clinical spectrum of congenital erythropoietic porphyria (CEP) ranges from nonimmune hydrops fetalis as a result of severe hemolytic anemia in utero to late-onset mild cases where the only symptoms are cutaneous lesions in the adult. The presence of large amounts of porphyrins in CEP very early in life, at the time of teeth and bone development, results in erythrodontia due to deposition of porphyrins in the developing teeth [Figure 4]. This is almost pathognomonic of CEP.[1] The photoactive nature of porphyrin molecules results in the bright pink fluorescence of these pigments in urine, teeth, and bones under Wood's lamp illumination. Hemolytic anemia can be mild or severe and may result in gallstones, splenomegaly, osseous fragility, and compression fractures. Hypertrichosis may often lead to what is sometimes called the ‘werewolf syndrome.’ Phototoxicity is characteristically very severe, leading to the formation of blisters and recurrent atrophic scars that result in characteristic mutilation. Figure 4 Erythrodontia (Wood's lamp examination) 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 hemorrhages may also occur. In long-term cases, severe osteolysis accompanied with mutilation is found, associated with severe contraction and atrophy of the fingers, similar to one that occurs in scleroderma and resulting in acromicria. Answer 2 Congenital erythrocytic porphyria occurs due to deficiency of the enzyme uroporphyrinogen III synthase (URO-IIIs). It results in an increase in uroporphyrin I and coproporphyrin I in plasma, red blood cells, urine, feces, and in different tissues. The URO-III s gene is located on chromosome 10q25.2-q26.3 spanning 34 kb and encompassing 10 exons encoding a 265 amino acid protein. As a result of alternative splicing, there are two mRNAs expressed from the URO-III s gene; one is erythroid cell-specific and the other is expressed in all tissues and is referred to as the house-keeping form. The house-keeping transcript contains exon 1 and then exons 2B through 10 while the erythroid-specific transcript contains exons 2A and 2B through 10. Physiologically, URO-III s converts hydroxymethylbilane into uroporphyrinogen III. Several mutations have been identified in the URO-III s gene including missense, nonsense, and splicing mutations, large and small deletions and insertions. The most common mutation, occurring in about 35% of CEP patients, is a missense mutation leading to the substitution of arginine for cysteine at amino acid 73 (C73R). The URO-III s is one of the enzymes responsible for the synthesis of heme in erythrocytes. In URO-III s deficiency almost 85% of hydroxymethylbilane spontaneously condenses into isomer I or biologically inactive uroporphyrin I (UROI), while 15% condenses into isomer III (uroporphyrinogen III).[2] Uroporphyrins and other metabolic deposits in the skin produce oxidative damage when exposure to light occurs. Answer 3 Epidermolysis bullosa, erythropoietic protoporphyria (EPP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), and pseudoporphyria, all these form a close differential diagnosis to CEP due to the presence of blistering, scarring, and mutilation. By attending to following features right diagnosis can be reached. In CEP, classical presentation is in infancy with red urine in diaper. HEP usually presents in childhood and has elevated levels of protoporphyrins in erythrocytes. PCT is the most common human porphyria, usually presents in mid or late life. EPP is distinguishable by nonblistering and immediate photosensitivity usually early in life. Pseudoporphyria, is a bullous photodermatosis in the absence of abnormalities in porphyrin metabolism. High index of suspicion in all cases of photosensitivity, abdominal pain, and unexplained seizures should be kept for diagnosis of porphyria. Confirmation of the diagnosis of cutaneous porphyria can be made by initial screening of the total porphyrin with a spectrophotometer or a spectrofluorometer. The specimens analyzed are urine and plasma or feces.[3] Exact typing of porphyrias can be done with high-pressure liquid chromatography (HPLC). In CEP, urinary porphyrins may increase from 100 to 1,000 times. URO I, uroporphyrin III, and coproporphyrin III are also increased. Diagnosis of erythropoietic protoporphyria is based on the detection of increased levels of free protoporphrin IX in red blood cells. (reference value less than 40 mcg/100mL using the hematofluorometric method). The excretion of precursors of delta aminolevulinic acid and porphobilinogen are normal in CEP. Measuring enzymes in cells and looking for changes (mutations) in DNA is useful for confirmation and for family studies. Answer 4 Management is mostly symptomatic. Total abstinence from sun exposure is important to prevent cutaneous neoplasms, one of the complications of CEP.[4] Therapeutic interventions include β-carotene, activated charcoal, hydroxyurea, corticosteroids, splenectomy, transfusion regimens, and intravenous hematin therapy to suppress hemoglobin production by a negative feedback mechanism. The benefit of blood transfusion decreases during puberty when hormonal changes increase the biosynthesis of heme. Bone marrow transplantation substitutes the erythroblasts of the medulla and produces normal levels of URO- III s and reverses the disease manifestations.[5] Stem cell transplantation and gene therapy are new avenues of treatment. Learning Points Familiarity with disease presentation is a key to early diagnosis and management. Symptoms and signs are due to accumulated porphyrins in the teeth and bones and in the plasma, bone marrow, feces, red blood cells, and urine. Disease manifestations need to be looked for in skin, eyes, bones, teeth and urine. Features like blistering, scarring, discoloration of the skin, ectropion, complete loss of eyelashes, and eyebrows, corneal scarring, scleromalacia, atrophy of the optic nerve and retinal hemorrhages may also occur. Bone and teeth involvement present as mutilation, severe contracture, atrophy of the fingers, and erythrodontia and urine that is red in color. Neuromuscular system needs focus to discern any evidence of seizures, muscle pain, weakness or paralysis, numbness and/or tingling, soreness in legs or arms, back pain, exaggerated deep tendon reflexes and even some changes in personality Avoiding sun exposure, skin injuries, stress, alcohol, smoking, and fasting and taking a high carbohydrate diet are beneficial.