Statistics from Altmetric.com
Editor,—Congenital erythropoietic porphyria (CEP: MIM No 263700) is an extremely rare disorder inherited as an autosomal recessive trait, which is characterised by an 80–98% reduction in the activity of uroporphyrinogen III synthase (UROS: EC 22.214.171.124).1Clinically, CEP is characterised by severe cutaneous photosensitivity, chronic haemolysis, and massive porphyrinuria resulting from the accumulation in the bone marrow, peripheral blood, and other organs of large amounts of the non-physiological and pathogenic porphyrin isomers, uroporphyrin I and coproporphyrin I.2 Red urine may be observed from infancy, and the teeth become stained red. Haemolytic anaemia, an additional complication, may be helped by splenectomy. Besides such manifestations, we reported a scleral change in the patient with CEP,3 who had a remarkable increase of porphyrins in tear drops. Our case report strongly suggests that the accumulation of porphyrins in tear drops may directly cause the scleral changes in the patients with CEP.
A 24 year old man presented typical manifestations of CEP such as skin ulcer and scaring. He was diagnosed with CEP in childhood, because of the elevation of porphyrins in urine. At the time of visit, slit lamp examination of bulbar conjunctiva revealed irregular hypertrophy between palpebral fissures in both eyes. A 3 × 4 mm area of scleral necrosis was observed at the limbus in the right eye (Fig 1). Hypertrophy of the temporal limbus and pigmentation of eyelids were also observed, but lid closure was normal. Corneal changes were not observed. Visual activity was right eye: 20/50, left eye: 20/20.
In order to cover the region of scleral necrosis, amniotic membrane grafting was performed, but postoperative wound healing was slow and the graft filed to be attached. Histological finding with a tissue taken during this operation showed an inflammatory infiltration of neutrophils and plasma cells in connective tissue under conjunctival layer (data not shown).
To confirm whether this scleral necrosis is caused by the direct effect of the accumulation of porphyrins in tear drops, analysis of tear drop porphyrins was performed after obtaining informed consent. In normal control, no porphyrin isomers were observed, whereas in this patient, remarkable elevations of type I porphyrins and protoporphyrin were observed (Fig 2).
Furthermore, sequence analysis of UROS was performed and an A to G transition of nucleotide 184 that predicted a threonine to alanine substitution at residue 62 (T62A), and a C to T transition of nucleotide 745 that predicted a glutamine to premature stop codon (Q249X). These mutations have been previously reported by Xuet al.4
This patient was confirmed to have compound heterozygous mutations, T62A/Q249X. These mutations had been described by Xuet al in a Japanese patient with CEP.4 They performed in vivo expression study for each mutation, and confirmed that each of them had no residual activity. We can expect that both mutations in this case are “disease causative.”
Scleral changes at the body surface lesions in CEP are mainly caused by the accumulation of porphyrins.4 Here we proved the accumulation of porphyrins in tear drops with a single case of CEP. Additional cases are needed to confirm the presence of porphyrins in tear drops although they are asymptomatic for eye involvement. Since our finding demonstrates the likelihood that accumulated porphyrins in tear drops directly exerted a toxic effect in scleral lesions, the protection of sunlight by ultraviolet cut glasses is strongly recommended for prevention against the initiation and progression of scleral lesions in the patients with CEP.