Última actualización:
7/23/2024
Años publicados: 1987, 1988, 1990, 1996, 1997, 2000, 2010, 2016, 2020, 2024
NORD gratefully acknowledges Angelika L. Erwin, MD, PhD, Medical Geneticist, Center for Personalized Genetic Healthcare, Cleveland Clinic; Assistant Professor of Pediatrics, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University and Robert J. Desnick, PhD, MD, Dean for Genetics and Genomic Medicine Emeritus, Professor and Inaugural Chairman Emeritus, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, for the preparation of this report.
Summary
Congenital erythropoietic porphyria (CEP) is a very rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen III synthase (UROS), the fourth enzyme in the heme biosynthetic pathway. Due to the impaired function of this enzyme, excessive amounts of certain porphyrins accumulate, particularly in the bone marrow, plasma, red blood cells, urine, teeth and bones. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the photo-activated porphyrins in the skin cause bullae (blistering), the fluid-filled sacs rupture and the lesions often get infected. These infected lesions can lead to scarring, bone loss and deformities. The hands, arms and face are the most commonly affected areas. CEP is inherited as an autosomal recessive genetic disorder. Typically, there is no family history of the disease. Neither parent has symptoms of CEP, but each carries a gene variant that they can pass to their children. Affected offspring have two copies of the disease-causing gene variant, one inherited from each parent.
Introduction
CEP is one condition of a group of disorders known as the porphyrias. Each porphyria is characterized by abnormally high levels of porphyrin precursors or porphyrins in the body due to deficiency or overactivity of certain enzymes in the stepwise synthesis of heme, the essential component of hemoglobin and various hemoproteins. The porphyrias can be classified as cutaneous or acute, depending on their respective symptoms. There are eight major porphyrias. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient or overactive. People who have one type of porphyria do not develop the other types, although very rarely, patients may have two different porphyrias.
The most common symptom of CEP is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with blistering of the skin occurring after sun or light exposure. Affected areas of the skin may develop blisters (vesicles or bullae) which may become infected, scar and/or become discolored (hyperpigmentation) if exposure to sunlight is prolonged. These affected areas of skin may become abnormally thick. In addition, some affected individuals may also have loss of nails and end digits of the fingers due to infection of the underlying bone. Loss of facial features such as lips, parts of the ears and nose can also occur. The severity and degree of photosensitivity differ depending on the severity of the patient’s deficient enzyme activity which correlates with the individual gene variants. Photosensitivity often occurs from birth; however, in some people, it may not occur until childhood, adolescence or adulthood. Patients also often have brownish discolored teeth (erythrodontia) which fluoresces under ultraviolet light as well as increased hair growth (hypertrichosis).
In more severely affected patients, other symptoms can include a low level of red blood cells (anemia) and enlargement of the spleen. The anemia can be severe, and these patients require periodic blood transfusions to maintain sufficient numbers of red blood cells. In severely affected patients, anemia may be present in the fetus. Ocular problems also can occur including corneal scarring, eye inflammation and infections.
Symptoms usually start in infancy or childhood and the diagnosis in most patients is suggested by the reddish color of the urine which stains the diapers.
CEP is caused by variants in the UROS gene that produces the UROS enzyme. The symptoms of CEP develop due to excessive levels of the specific porphyrins that accumulate in tissues of the body because of the markedly impaired function of the UROS enzyme.
Congenital erythropoietic porphyria is usually inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
One female patient has been reported in the medical literature with very severe CEP symptoms was found to have two variants in the UROS gene and in addition, she also had a variant in a gene called ALAS2, which is usually associated with another form of cutaneous porphyria (X-linked protoporphyria). It is assumed that this additional gene variant in the ALAS2 gene is the reason why her CEP symptoms were more severe than expected.
In very rare cases, one particular variant in another gene called GATA1 has been found to cause CEP. So far, three CEP patients have been reported with the GATA1 gene variant who do not have a variant in the UROS gene. GATA1 is located on the X chromosome, which means that males with a CEP-causing variant in this gene will develop CEP symptoms while female carriers may remain asymptomatic or have less severe symptoms. This is because males have one X chromosome whereas females have two.
Inheritance of GATA1-related CEP is X-linked. X-linked genetic disorders are conditions caused by a disease-causing gene variant on the X chromosome and mostly affect males. Females who have a disease-causing gene variant on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the gene variant. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease-causing gene variant, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
CEP is a very rare genetic disorder that affects males and females in equal numbers. Over 200 patients have been reported worldwide.
The diagnosis of CEP may be suspected when reddish-colored urine is noted at birth or later in life. This finding, or the occurrence of skin blisters on sun or light exposure, should lead to a thorough clinical evaluation and specialized laboratory tests. The diagnosis can be made by testing the urine for increased levels of specific porphyrins. The diagnosis can be confirmed with testing that identifies the specific UROS enzyme deficiency and/or genetic testing that identifies variants in the UROS gene.
Prenatal and preimplantation genetic diagnosis are available for future pregnancies in CEP families if the underlying genetic variants are known.
Treatment
Avoidance of sunlight is essential to prevent the skin lesions in individuals with CEP. The use of topical, zinc- or titanium-oxide containing sunscreens, protective clothing, long sleeves, hats, gloves and sunglasses are strongly recommended. Individuals with CEP benefit from window tinting or using vinyls or films to cover the windows in their car or home. Before tinting or shading car windows, affected individuals should check with their local Registry of Motor Vehicles to ensure that such measures do not violate any local codes.
Individuals with CEP are at risk for low bone density and may be more likely to experience bone fractures. Especially due to the avoidance of sun exposure, all CEP patients should take vitamin D supplements.
In addition to protection from sunlight, anemia should be treated if present. Chronic blood transfusions have been useful in decreasing the bone marrow production of phototoxic porphyrins but must be used with caution due to complications associated with chronic transfusion therapy.
When successful, bone marrow or hematopoietic stem cell transplantation can cure patients with CEP, but these procedures have a risk for complications and death.
Referral to a porphyria center is recommended for expert diagnosis, care and genetic counseling.
The Rare Diseases Clinical Research Network (RDCRN), funded by the National Institutes of Health (NIH) and the Office for Rare Diseases Research (ORDR), is sponsoring The Porphyrias Consortium. This Consortium brings together porphyria experts at six academic institutions and eight satellite sites, the United Porphyrias Association and industry to carry out clinical studies and clinical trials to accelerate the development of improved diagnosis and treatment for the patients with these rare diseases.
For more information:
The Porphyrias Consortium of the Rare Diseases Clinical Research Network:
https://www.rarediseasesnetwork.org/cms/porphyrias
United Porphyrias Association:
https://www.porphyria.org/
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All U.S. studies are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
To-Figueras J, Erwin AL, Aguilera P, Millet O, Desnick RJ. Congenital erythropoietic porphyria. Liver Int. 2024;doi: 10.1111/liv.15958. Online ahead of print.
Bernardo-Seisdedos G, Charco JM, SanJuan I, García-Martínez S, Urquiza P, Eraña H, Castilla J, Millet O. Improving the Pharmacological properties of ciclopirox for its use in congenital erythropoietic porphyria. J Pers Med. 2021;11(6):485.
Blouin JM, Ged C, Bernardo-Seisdedos G, Cabantous T, Pinson B, Poli A, Puy H, Millet O, Gouya L, Morice-Picard F, Richard E. Identification of novel UROS mutations in a patient with congenital erythropoietic porphyria and efficient treatment by phlebotomy. Mol Genet Metab Rep. 2021;27:100722.
Erwin AL, Balwani M. Porphyrias in the age of targeted therapies. Diagnostics (Basel). 2021;11(10):1795.
Erwin AL, Desnick RJ. Congenital erythropoietic porphyria: Recent advances. Mol Genet Metab. 2019;128(3):288-297.
Christiansen AL, Aagaard L, Krag A, Rasmussen LM, Bygum A. Cutaneous porphyrias: causes, symptoms, treatments and the Danish incidence 1988-2013. Acta Derm Venereol. 2016;96:868-872.
Di Pierro E, Brancaleoni V, Granata F. Advances in understanding the pathogenesis of congenital erythropoietic porphyria. Br J Haematol. 2016;173:165-379.
Di Pierro E, Russo R, Karakas Z, Brancaleoni V, Gambale A, Kurt I, Winter SS, Granata F, Czuchlewski DR, Langella C, Iolascon A, Cappellini MD. Congenital erythropoietic porphyria linked to GATA1-R216W mutation: challenges for diagnosis. Eur J Haematol. 2015;94:491-497.
Egan DN, Yang Z, Phillips J, Abkowitz JL. Inducing iron deficiency improves erythropoiesis and photosensitivity in congenital erythropoietic porphyria. Blood. 2015;126:257-261.
Baran M, Eliacik K, Kurt I, Kanik A, Zengin N, Bakiler AR. Bullous skin lesions in a jaundiced infant after phototherapy: a case congenital erythropoietic porphyria. 2013;55:218-221.
Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012;120(23):4496-504.
Katugampola RP, Badminton MN, Finlay AY, Whatley S, Woolf J, Mason N, Deybach JC, Puy H, Ged C, de Verneuil H, Hanneken S, Minder E, Schneider-Yin X, Anstey AV. Congenital erythropoietic porphyria: a single-observer clinical study of 29 cases. Br J Dermatol. 2012;167(4):901-13.
Katugampola RP, Anstey AV, Finlay AY, Whatley S, Woolf J, Mason N, Deybach JC, Puy H, Ged C, de Verneuil H, Hanneken S, Minder E, Schneider-Yin X, Badminton MN. A management algorithm for congenital erythropoietic porphyria derived from a study of 29 cases. Br J Dermatol. 2012;167(4):888-900.
To-Figueras J, Ducamp S, Clayton, J, et al. ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria. Blood 2011;118:1443
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;109:618-2621.
Desnick RJ, Astrin KH. Congenital erythropoietic porphyria: advances in pathogenesis and treatment. Br J Haematol. 2002;117(4):779-95.
Harada FA, Shwayder TA, Desnick RJ, Lim HW. Treatment of severe congenital erythropoietic porphyria by bone marrow transplantation. J Am Acad Dermatol. 2001;45(2):279-82.
Tezcan I, Xu W, Gurgey A, Tuncer M, Cetin M, Oner C, et al. Congenital erythropoietic porphyria successfully treated by allogeneic bone marrow transplantation. Blood. 1998;92(11):4053-8.
Fritsch C, Bolsen K, Ruzicka T, Goerz G. Congenital erythropoietic porphyria. J Am Acad Dermatol. 1997;36(4):594-610.
INTERNET
Erwin A, Balwani M, Desnick RJ; Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network. Congenital Erythropoietic Porphyria. 2013 Sep 12 [Updated 2021 Apr 15]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK154652/ Accessed May 21, 2024.
Congenital Erythropoietic Porphyria. Online Mendelian Inheritance in Man (OMIM). Entry No:263700; Last Edit: 05/29/2019. http://www.omim.org/entry/263700. Accessed May 21, 2024.
Hebel JL and Poh-Fitzpatrick MB. Congenital Erythropoietic Porphyria. Medscape. Updated: May 24, 2018. http://emedicine.medscape.com/article/1103274-overview Accessed May 21, 2024.
NORD y la Fundación MedicAlert se han asociado en un nuevo programa para brindar protección a pacientes con enfermedades raras en situaciones de emergencia.
Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.
Aprende más https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/Este programa de asistencia, primero en su tipo, está diseñado para los cuidadores de un niño o adulto diagnosticado con un trastorno raro.
Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View report