INTRODUCTION

Congenital erythropietic porphyria (CEP), or Gunther’s disease, is one of the rarest of the porphyrias, estimating a prevalence of < 0.9 in 1,000,000 [1,2]. It is a severe autosomal recessive form of the disease caused by uroporphyrinogen III synthesis deficiency and responsible for the accumulation of the non-physiologic porphyrinogen I isomers, uroporphyrinogen I and coproporphyrinogen I, in the bone marrow, red blood cells, teeth, and dermis. These metabolites are excreted and oxidized in the urine and feces as uroporphyrin I and coproporphyrin I and lead to visceral symptoms of hemolysis and splenomegaly and/or hypo-/hyper-pigmented areas, hypertrichosis, scarring, bullae, and vesicles on sun-exposed regions of the skin, as well as tooth manifestations [3,4].

Lifelong bullous cutaneous photosensitivity to visible light and skin fragility begin in early infancy, leading to scarring with photomutilation. Disease severity in CEP may range from fetal hydrops in utero to adult-onset mild cutaneous photosensitivity [5,6].

Herein, we present the case of a two-year-old Moroccan female suffering from excessive photosensivity who was diagnosed with CEP.

CASE REPORT

A two-year-old female born of a consanguineous marriage was referred to our training for bullous lesions of the face, dorsal surfaces of the hands and feet giving way to sequellary dyschromic spots.

The symptoms began in her first months of life, when her mother noticed reddish-colored urine in the diaper, followed by constatation also of reddish-brown color of the first teeth, for which the parents did not consult. The evolution was marked one year later by the appearance of bullous lesions leaving atrophic and pigmented scars, mainly located in sun-exposed areas.

The patient had one healthy sister, and the other members of the family had no similar findings.

A physical examination revealed tense and hemorrhagic bullae occurring on the normal-appearing skin of the feet. In addition, all sun-exposed areas showed hyper- and hypo-pigmentation, residual atrophic scars, and hypertrichosis, especially on the patient’s cheeks and forehead (Fig. 1).

Figure 1: Atrophic and pigmented scars of the hands.

The teeth were discolored appearing reddish-brown (erythrodontia) under visible light, yet no other lesions were detected in the oral cavity. Fluorescence spectroscopy using Wood’s lamp revealed spontaneous bright red fluorescence of the teeth and urine (Figs. 2 – 3). Abdominal examination did not reveal splenomegaly or hepatomegaly.

	Figure 2: (a) Erythrodontia and (b) spontaneous bright red fluorescence under Wood’s light.
	Figure 3: (a and b) Spontaneous bright red fluorescence of urine under Wood’s lamp.

Her biological workup was compatible with regenerative anemia at 10.10 g/dL, her liver enzymes and lactic dehydrogenase (LDH) were normal, and haptoglobin was collapsed at 0.08 g/L (normal 0.3-2g/L) with anisopoikylocytosis on blood smear.

The porphyrin profile in her urine revealed elevated uroporphyrins and coproporphyrin-I.

Based on the patient’s history, clinical examination, and lab work, we diagnosed the patient with CEP.

We informed the parents about the disease of their daughter and the importance of strict photoprotection. She and her sister were HLA-typed. While awaiting these results, we recommended using high sun protection factor sunscreens and oral charcoal.

DISCUSSION

Congenital erythropoietic porphyria was published first by Schultz in 1874. It was described in detail in 1911 by Gunther and termed Gunther’s disease [7]. It is an autosomal recessive disorder of the porphyrin metabolism caused by decreased activity of uroporphyrinogen III cosynthase [8]. The Urogen III synthase is encoded by the UROS gene located on chromosome 10q26.2 [9], the biallelic mutation of which would be responsible for a deficit in the activity of the fourth enzyme in the heme synthesis cycle (Urogen III synthase) and, therefore, responsible for the majority CEP cases.

Recently, it has been shown that several mutations in other genes may be implicated in the pathogenesis, such as the GATA1 and aminolevulinate synthase genes, which may also explain the X-linked inheritance pattern [2,10]. There is a close correlation between different mutations, the reduction of Urogen III synthase activity, the accumulations and deficiencies of the heme cycle intermediates and the severity or mortality of the disease [11] (Table 1).

Table 1: Correlation between the different mutations.

In order to understand the pathophysiological mechanism of CEP, it is necessary to know the metabolism of porphyrins and the deficient enzyme to conclude in the type of porphyria. Normally, after formation in the cytosol of hydroxymethylbilane (HMB) by condensation of four molecules of porphobilinogen, which also results from the condensation of two molecules of ALA, it will be rearranged and cyclized by UROS, which dominates the process to form the III isomeric form of uroporphyrinogen (uroporphyrinogen III). A fraction of hydroxymethylbilane escapes from the UROS action and undergoes a non-enzymatic conversion to I isomer form of uroporphyrinogen and, subsequently, coproporphyrinogen I [2,3].

In CEP, UROS is deficient leading to the accumulation of hydroxymethylbilane (HMB), most of which passes through the non-enzymatic conversion pathway to uroporphyrinogen I, which is metabolized in a minor part to coproporphyrinogen I and both accumulate in large amounts in the bone marrow, erythrocytes, plasma, the bones, and the teeth, where they undergo auto-oxidation to give uroporphyrin I (UROI) and coproporphyrin I (COPROI), respectively [4] and are excreted in feces and urine.

These porphyrins become photoreactive and absorb visible light energy, especially between 400 and 410 nm in wavelet and pass to a higher excited state and induce free radicals that damage the involved tissue [2,3].

The severity and clinical manifestation of CEP are correlated with porphyrin profiles and the degree of their excess [12]. It may begin during pregnancy and lead to hydrops fetalis and death in utero. Skin photosensitivity most often begins in the first days of life and reddish urine in the diaper with intensive pink fluorescence under Wood’s lamp is the earliest sign [13], followed by the formation of vesicles and bullae on sun-exposed areas, which are prone to be ruptured, leading to erosions and ulcerations, which might become infected leading to scarring and facial disfigurement [3,14].

Other skin complications may occur as areas of hypo- and/or hyperpigmentation, facial hypertrichosis, epidermal atrophy, scleroderiform appearance, and scarring alopecia [14,15]. The nails may also be affected and manifested by subungual blisters, longitudinal ridging, onycholysis, and anonychia associated with discoloration of the teeth (erythrodontia) as in our case, microstomia, and dental caries [14]. Other devices may be affected with ocular involvement ranging from photophobia or blepharitis to blindness [16], skeletal changes such as acroosteolysis, osteopenia and osteoporosis, systemic signs such as hemolytic anemia, hepatomegaly, neonatal jaundice, splenomegaly, and secondary pancytopenia [14]. Neurological manifestations are not common in CEP, yet at the same time, it was reported that chronic and excessive production of porphyrins and their accumulation in the meninges and brain could be responsible for neurodegenerative disorders [14].

Besides the above-described clinical signs, there are biochemical characteristics of CEP decreased activity of UROGEN III synthase, elevated levels in erythrocytes, urines, plasma, and feces of uroporphyrins and coproporphyrins type I isomer [3].

Prenatal diagnosis of CEP is now possible by analysis of amniotic fluid and measurement of uroporphyrins I and amniotic cells UROGEN III cosynthase activity [17].

Since the discovery of CEP, numerous symptomatic treatments have been tried as oral ß-carotene, p-aminobenzoate, chloroquine, and zinc sulfate without proven efficiency [18]. The administration of oral charcoal is also included in symptomatic treatment, whose mechanism consists of binding to porphyrins and interfering in their enterohepatic circulation and rapidly reducing their plasma concentrations [4,19], as it was done in our patient. Iterative transfusions are effective in forms with hemolysis to inhibit the overproduction of porphyrins by feedback repression of ALA synthase, yet their complications such as infections and hemolytic crisis leading to splenomegaly limit their use. In our case, hemolysis and moderate anemia did not require the use of these therapies.

The only curative treatment is hematopoietic stem cell transplantation, originating from the marrow bone, peripheral blood, or umbilical cord blood [20]. In the absence of a compatible HLA donor, an alternative by gene therapy is under study in humans.

CONCLUSION

This case demonstrates many of the cutaneous manifestations and biochemical characteristics of CEP in a patient with a moderate form and who was under symptomatic and preventive treatment while awaiting allogeneic bone marrow transplantation.

REFERENCES

1.Stölzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019;157:365-81.

2.Di Pierro E, Brancaleoni V, Granata F. Advances in understanding the pathogenesis of congenital erythropoietic porphyria. Br J Haematol. 2016;173:365-79.

3.Desnick RJ, Astrin KH. Congenital erythropoietic porphyria:Advances in pathogenesis and treatment. Br J Haematol. 2002;117:779?95.

4.Pimstone NR, Gandhi SN, Mukerji SK. Therapeutic efficacy of oral activated charcoal in congenital erythropoietic porphyria. N Engl J Med. 1987;316:390.

5.Daîkha-Dahmane F, Dommergues M, Narcy F, Gubler MC, Dumez Y, Gauthier E, et al. Congenital erythropoietic porphyria:Prenatal diagnosis and autopsy findings in two sibling fetuses. Pediatr Dev Pathol. 2001;4:180-4.

6.Verstraeten L, Van Regemorter N, Pardou A, de Verneuil H, Da Silva V, Rodesch F, et al. Biochemical diagnosis of a fatal case of Günther’s disease in a newborn with hydrops foetalis. Eur J Clin Chem Clin Biochem. 1993;31:121-8.

7.Mason VR, Farnham RM. Acute hematoporphyria:Report of two cases. Arch Intern Med (chic). 1931;47:467-83.

8.Pannier E, Viot G, Aubry MC, Grange G, Tantau J, Fallet-Bianco C, et al. Congenital erythropoietic porphyria (Gunther’s disease):Two cases with very early prenatal manifestation and cystic hygroma. Prenatal Diagnosis. 2003;23:25-30.

9.Aizencang G, Solis C, Bishop DF, Warner C, Desnick RJ. Human uroporphyrinogen-III synthase:Genomic organization, alternative promoters, and erythroid-specific expression, Genomics. 2000;70:223-31.

10.Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP. Congenital erythropoietic porphyria due to a mutation in GATA1:The first trans-acting mutation causative for a human porphyria. Blood. 2007;109:2618-21.

11.Lambert CR, Reddi E, Spikes JD, Rodgers MA, Jori G. The effects of porphyrin structure and aggregation State on photosensitized processes in aqueous and micellar media. Photochem Photobiol. 1986;44:595-601.

12.Freesemann AG, Bhutani LK, Jacob K, Doss MO. Interdependence between degree of porphyrin excess and disease severity in congenital erythropoietic porphyria (Günther’s disease). Arch Dermatol Res. 1997;289:272-6.

13.Pollack SS, Rosenthal MS. Images in clinical medicine:Diaper diagnosis of porphyria. New Engl J Med. 1994;330:114.

14.Katugampola RP, Badminton MN, Finlay AY, Whatley S, Woolf J, Mason N, et al. Congenital erythropoietic porphyria:A single-observer clinical study of 29 cases. Br J Dermatol. 2012;167:901-13.

15.Fritsch C, Bolsen K, Ruzicka T, Goerz G. Congenital erythropoietic porphyria. J Am Acad Dermatol. 1997;36:594-610.

16.Veenashree MP, Sangwan VS, Vemuganti GK, Parthasaradhi A. Acute scleritis as a manifestation of congenital erythropoietic porphyria. Cornea. 2002;21:530-1.

17.Ged C, Moreau-Gaudry F, Taine L, Hombados I, Calvas P, Colombies P, et al. Prenatal diagnosis in congenital erythropoietic porphyria by metabolic measurement and DNA mutation analysis. Prenatal Diagn 1996;16:83-6.

18.Dawe SA, Peters TJ, Du Vivier A, Creamer JD. Congenital erythropoietic porphyria:Dilemmas in present day management. Clin Exp Dermatol. 2002;27:680-3.

19.Tanigawa K, Namba H, Ohtsuru A, Shima M, Nakata K, Kondo M, et al. Plasmasorbent therapy with activated charcoal column for congenital erythropoietic porphyria. Dermatology. 1994;188:329-30.

20.Thomas C, Ged C, Nordmann Y, de Verneuil H, Pellier I, Fisher A, et al. Correction of congenital erythropoietic porphyria by bone marrow transplantation. J Pediatr. 1996;129:453-6.