PD13 Severe cutaneous manifestations in an Indian child with X-linked dominant erythropoietic protoporphyria

Abstract

Abstract Erythropoietic protoporphyria (EPP) is usually caused by autosomal dominant mutations in FECH: raised protoporphyrin levels cause itching, burning and erythema after sun exposure, with facial scarring and sometimes liver damage. We report a child with the much rarer X-linked dominant form (XLDPP) and consider reasons for his unusually severe features. A 4-year-old boy living in India presented with long-standing erosions and scarring on the face and sides of the feet, and marked distal onycholysis with subungual hyperkeratosis affecting all nails, suggestive of pachyonychia congenita (PC). There was no relevant family history or parental consanguinity. He was anaemic (haemoglobin 7.2 g dL−1). Genetic testing revealed no variants in PC genes, but there was a hemizygous deletion in ALAS2, c.1706_1709del (p.Glu569GlyfsT er24) reported recurrently in XLDPP. Further review revealed a history of photosensitivity, low vitamin D3 and raised liver enzymes. Measurement of erythrocyte protoporphyrin was not available, but XLDPP was diagnosed on the basis of photosensitivity, liver abnormalities, probable photo-onycholysis and genetic testing. ALAS2 encodes 5-aminolaevulinate synthase, the first enzyme in the haem synthetic pathway. Most ALAS2 mutations block haemoglobin production resulting in sideroblastic anaemia. However, specific deletions, including this one, activate the pathway, increasing protoporphyrin to levels higher than what can be used in haematopoiesis. The manifestations of XLDPP therefore resemble EPP: protoporphyrin accumulation is caused in the former by increased production and in the latter by a block in its conversion to haem. Iron deficiency, common in Indian children, reduces haem production and consequently protoporphyrin utilization, potentially exacerbating the protoporphyrin accumulation caused by XLDPP. In a previous patient with XLDPP and anaemia due to gastrointestinal bleeding, iron therapy successfully lowered red cell protoporphyrin levels (Whatley SD, Ducamp S, Gouya L et al. C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet 2008; 83:408–14). Nail dystrophy has not previously been reported in XLDPP. The appearance here is consistent with photo-onycholysis in a child whose feet are always exposed in sandals. The delay in diagnosing photosensitivity and severity of his skin changes can be attributed to the difficulty in interpreting symptoms in young children and to local conditions where sun exposure is unavoidable. Management here involves iron therapy, photoprotection, monitoring of liver function and genetic counselling; female carriers may also have symptoms. We are grateful to national experts for helpful discussion of this case.