AUTOSOMAL RECESSIVE ERYTHROPOIETIC PROTOPORPHYRIA WITHOUT IVS3-48C IN TWO BROTHERS WITH LIVER DYSFUNCTION IN EARLY CHILDHOOD

F.W.M. de Rooij, K. Munte, A. Edixhoven, R. Koole, J.H.P. Wilson

Erasmus MC, Rotterdam, The Netherlands

Erythropoietic protoporphyria (EPP) is characterized by acute photosensitivity of sun-exposed skin from childhood. It results from partial deficiency of ferrochelatase (FECH), which leads to accumulation of protoporphyrin IX. Most patients with EPP have the combination of a low expression FECH allele (IVS3-48C/T in intron 3)  trans to a severe mutation. Mutations on both alleles have been identified in only a small number of patients.

Case reports: A young boy (A) presented at 3 years of age with painful erythema and swelling of sun-exposed skin during the summer months. There was no family history of photosensitivity. On examination, there was erythema of the face and back of the hands with areas of scarring and hypopigmentation. His erythrocyte protoporphyrin (PP) concentration was increased. His younger brother (B) also presented with similar complaints during the summer months from the 1st year of age. He too was found to have varioliform scars on his face and hands. Sunblock creams and protective clothing were advised and beta-carotene prescribed. Although initially normal, biochemical tests of liver function became progressively abnormal at 3 and 2 years of age respectively. Erythrocyte PP concentrations, FECH gene analysis, FECH activity in lymphoblastoid cell lines and transaminase levels are given in the table.

Ery. PP µmol/l

FECH

pmol/mg

IVS3-48

FECH  allele 1

FECH allele 2

AST   U/l

ALT  U/l

A

112,8

78

tt

Cys441Phe

His338Asn

163

259

B

136

46

tt

Cys441Phe

His338Asn

161

205

Mother

1,5

404

tt

Cys441Phe

n

-

-

Father

1,6

469

tt

n

His338Asn

-

-

Controls

< 1,5

>355

(tt)

n

n

< 56

< 39

 

Neither child, nor their parents, has the FECH IVS3-48C low expression allele. Both children are compound heterozygotes for mutations in the FECH gene, while their parents are carriers of one mutation each. Both children have markedly reduced FECH activity, and high erythrocyte free PP levels. In addition both children have a microcytic anemia (hemoglobin 6,6-6,8 mmol/l, n = 6,8 – 8,1; MCV 65 fL, n = 75 – 93), and low ferritin levels (12-13 µg/l, n = 30 - 240).

Conclusion: These two children have severe EPP, with markedly reduced ferrochelatase activity and abnormal liver function tests developing at a very early age. These findings support the suggestion that autosomal recessive EPP might carry a greater risk for liver damage than the more usual combination of a mutation and a low expression allele.