Genetic studies by NGS Panels
Panel for Congenital Erythropoietic Protoporphyria and Congenital erytropoietic Porphyria (Code 10080)
Congenital Erythropoietic Protoporphyria
Erythropoietic Protoporphyria (EPP) is an inherited disorder of heme metabolism, characterized by the accumulation of protoporphyrin in blood, erythrocytes and tissues, and by photosensitivity skin manifestations.
EPP has been described worldwide, with a prevalence ranging from 1 / 75,000 to 1 / 200,000.
It usually manifests in early childhood after the first exposure to the sun. EPP is characterized by cutaneous manifestations of acute painful photosensitivity, with erythema and edema, sometimes with petechia, together with pruritus and burning sensations without blistering, when exposed to sunlight or artificial light (400-700 nm). These episodes vary in severity depending on the duration of exposure and may result in permanent chronic lesions in the exposed skin area. Since protoporphyrin is a lipophilic molecule excreted by the liver, patients with EPP are at risk for cholelithiasis with obstructive episodes, and chronic liver disease that can progress to acute liver failure.
EPP is a lifelong disorder, whose prognosis depends on the progression of liver disease. However, photosensitivity can have a significant impact on the quality of life of patients with EPP.
In most patients, EPP is a consequence of a partial deficiency of the last enzyme in the heme biosynthesis pathway (coded by the FECH gene (18q21.2-q21.3) .EPP appears to be inherited as an autosomal dominant disease, whose clinical expression is modulated by the presence of the transhipomorphic allele IVS3-48C in the FECH gene, although recessive inheritance with two mutated FECH alleles has also been described.
In approximately 2-5% of patients, the disease has been shown to be caused by function-gain mutations in the aminolevulinic acid synthetase 2 gene, ALAS2 gene (Xp11.21); In this case the disease is called X-linked dominant protoporphyria.
Diagnosis is established by detecting the increase in the plasma protoporphyrin level and red blood cells, and by a plasma fluorescence peak at 634 nm. It is advisable to investigate hepatic involvement, the level of ferrochelatase activity, genetic analyzes (mutations in FECH, presence of the transhipomorphic allele IVS3-48C, and mutations in the ALAS2 gene) and family studies.
The differential diagnosis should include phototoxic reactions to drugs, hydroa vaciniform, solar urticaria, contact dermatitis, angioedema and, in some cases, other types of porphyria.
Congenital erytropoietic Porphyria
Congenital erythropoietic porphyria, or Günther’s disease, is a form of erythropoietic porphyria characterized by a very severe and mutilating photodermatosis.
Since its description at the end of the 19th century, around 200 cases have been reported in the literature.
The disease manifests itself more frequently at birth with extreme cutaneous photosensitivity that is severe and mutilating. The main signs are bumpy and rapidly erosive skin lesions on the surface of the skin exposed to the sun and light (hands, face, feet). Urine is often very red / brown and colors the diaper of affected children. In very severe forms, patients present haemolysis of different severity. Significant splenomegaly may occur, related to hemolytic anemia. Bone involvement is constant, with involvement of the bone architecture and risk of multiple fractures.
In severe forms hemolytic anemia and, in particular, thrombocytopenia dominate the prognosis and considerably shorten the life expectancy of patients. Multiple fractures often cause mobility impairment. Recently, bone marrow transplantation has dramatically improved the prognosis of congenital erythropoietic porphyria (especially if the patient is young) by healing cutaneous lesions and making haemolytic anemia disappear.
Congenital erythropoietic porphyria is caused by a deficiency of the enzyme uroporphyrinogen synthase (URO-S protein, fourth enzyme in the heme biosynthesis pathway) that leads to a massive accumulation of isomeric porphyrins I (uro and coproporphyrins) in the bone marrow. The enzymatic deficiency is caused by mutations of the UROS gene, which encodes URO-S. Transmission is autosomal recessive. It should be noted that there is some degree of genotype-phenotype correlation by identifying “severe” or “moderate” mutations. In 50% of cases the “severe” C73R mutation is present.
The diagnosis is based on evidence of a massive accumulation of isomeric porphyrins in the urine and blood. Evidence of a URO-S deficiency in red blood cells and the identification of causative mutations of the UROS gene allow for a confirmed diagnosis.
The differential diagnosis may include hepatoerythropytic porphyria.
- Deybach, J.-C., de Verneuil, H., Boulechfar, S., Grandchamp, B., Nordmann, Y. Point mutations in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria (Gunther’s disease). Blood 75: 1763-1765, 1990. [PubMed: 2331520]
- Gouya, L., Deybach, J. C., Lamoril, J., Da Silva, V., Beaumont, C., Grandchamp, B., Nordmann, Y. Modulation of the phenotype in dominant erythropoieticprotoporphyria by a low expression of the normal ferrochelatase allele. Am. J. Hum. Genet. 58: 292-299, 1996. [PubMed: 8571955]
- Gross, U., Hoffmann, G. F., Doss, M. O. Erythropoietic and hepatic porphyrias. J. Inherit. Metab. Dis. 23: 641-661, 2000. [PubMed: 11117426]
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- Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H. 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. 83: 408-414, 2008. [PubMed: 18760763]