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Congenital erythropoietic porphyria

Congenital erythropoietic porphyria
Literature review current through: Jan 2024.
This topic last updated: Jan 20, 2022.

INTRODUCTION — The porphyrias are metabolic disorders caused by altered activities of enzymes within the heme biosynthetic pathway. Congenital erythropoietic porphyria (CEP; OMIM #263700, also called Günther disease) is a rare, autosomal recessive porphyria.

The pathophysiology, diagnosis, and management of CEP will be reviewed here [1]. A general overview of the porphyrias and detailed discussions of the other cutaneous porphyrias are presented separately. (See "Porphyrias: An overview" and "Erythropoietic protoporphyria and X-linked protoporphyria" and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

PATHOGENESIS

Enzymatic defect — CEP results from an inherited deficiency of the heme biosynthetic enzyme uroporphyrinogen III synthase (UROS; EC 4.2.1.75, hydroxymethylbilane hydrolase [cyclizing]; previously termed uroporphyrinogen III cosynthase) [2-4].

In patients with CEP, developing red blood cell precursors that are synthesizing hemoglobin have reduced UROS activity, which causes accumulation of pathogenic porphyrins (uroporphyrin I and coproporphyrin I). These porphyrins are nonphysiologic because they cannot be metabolized to heme. Porphyrins are also elevated in mature red blood cells, plasma, spleen, feces, teeth, and bones. These accumulated porphyrins cause hemolytic anemia and severe cutaneous photosensitivity. In addition, the teeth, bones, and urine of affected individuals are often red or brown and fluoresce on exposure to light, especially with a wavelength of 400 to 420 nm.

UROS is the fourth enzyme in the heme biosynthetic pathway. It catalyzes the conversion of the linear tetrapyrrole hydroxymethylbilane (HMB) to the cyclic tetrapyrrole uroporphyrinogen III (figure 1). This occurs with inversion of one of the four pyrroles, which becomes ring D of the product uroporphyrinogen III [5]. Patients with congenital erythropoietic porphyria (CEP) lack normal UROS activity, and as a result the HMB intermediate accumulates excessively in bone marrow red blood cell (RBC) precursors that are actively synthesizing hemoglobin. HMB does not accumulate in the liver or other tissues that synthesize heme.

Excess HMB is converted non-enzymatically (by spontaneous ring closure without inversion of pyrrole ring D) to the non-physiologic porphyrin isomer uroporphyrinogen I, some of which is then enzymatically converted by uroporphyrinogen decarboxylase (the fifth enzyme in the pathway) to coproporphyrinogen I. Coproporphyrinogen I cannot be metabolized further, because the next enzyme, coproporphyrinogen oxidase, is stereospecific for the coproporphyrinogen III isomer. The excess porphyrinogens that accumulate in CEP are oxidized non-enzymatically to the corresponding porphyrins, primarily uroporphyrin I and coproporphyrin I, which are markedly elevated and readily measured in circulating erythrocytes, plasma, urine and feces. These porphyrins are also deposited in teeth and bones.

Hemolysis — High porphyrin levels in erythrocytes are believed to be the cause of hemolysis in CEP. To compensate for hemolysis and ineffective erythropoiesis, heme and hemoglobin synthesis are actually increased, despite the severe deficiency of UROS. Hemolysis in severe cases of CEP is often associated with anemia, because the bone marrow cannot adequately compensate for ineffective erythropoiesis and/or the rapid rate of destruction of circulating RBCs. Although the level of hemolysis is likely to remain constant over time, the anemia may be exacerbated by nutrient deficiencies or during other illnesses. (See "Diagnosis of hemolytic anemia in adults", section on 'Atypical presentations'.)

Photosensitivity — Isomer I porphyrins produced in developing erythrocytes in CEP are released into the circulation in plasma and mature erythrocytes. Photosensitivity occurs because these porphyrins circulate to the skin and generate free radicals upon exposure to light. Porphyrins absorb wavelengths of light especially in the 400 to 420 nm range (ie, the Soret band for porphyrins), which is visible light close to the range of long wavelength ultraviolet light (ie, UVA; range 315 to 400 nm). Patients with CEP and other cutaneous porphyrias are sensitive to sunlight and to some extent fluorescent and even incandescent indoor lights. Window glass transmits this light (but not short wave ultraviolet light [ie, UVB]) and therefore is not protective. Porphyrins that are activated by light generate oxygen free radicals that damage cells and tissues, causing skin friability and blistering. If severe and continuous, accumulated damage to the skin can lead to scarring and mutilation. Superimposed bacterial infection contributes to mutilation. (See 'Clinical findings' below.)

UROS gene variants — CEP results from pathogenic variants in the UROS gene. A variety of variants in the UROS gene have been identified in patients with CEP. These include missense and nonsense mutations, large and small deletions and insertions, splicing defects, and intronic branch point mutations [6-17].

The majority of patients with CEP are heteroallelic (compound heterozygotes) for pathogenic variants in UROS. Most who are homoallelic for a single UROS variant have consanguineous parents. The role of UROS variants in CEP has been further demonstrated by mouse models in which knock-in of human UROS disease variants produced characteristic findings of the human disease [18,19].

In one study, the most common mutation, C73R, was found in approximately 33 percent of the studied alleles [11]. The next most common mutations were L4F and T228M (7 and 6 percent, respectively). Except for these, most other pathogenic variants have been detected in only one or a few CEP families.

In three unrelated males with CEP, beta-thalassemia, and thrombocytopenia, the gene encoding the GATA1 transcription factor, which affects UROS expression, was found to have a pathogenic variant, rather than the UROS gene itself [4,20]. In a few CEP patients, a pathogenic variant was not found in the UROS or GATA1 genes, so it is possible that in some cases additional gene(s) may play a role in CEP pathogenesis [4].

Genotype phenotype correlations — The level of the UROS enzyme varies dramatically depending on the specific UROS gene variant, from nondetectable to approximately 35 percent of normal enzyme activity [7,21-23]. Homoallelism for the most common allele, C73R, was correlated with the most severe phenotype, leading to non-immune hydrops fetalis and/or transfusion dependency from birth. The C73R mutation affects the stability of the UROS protein rather than its enzymatic activity, and the abnormal enzyme is subject to premature degradation via the proteosome; proteasome inhibitors or molecular chaperones represent a new therapeutic approach to treatment of the disease [24,25].

Heteroallelism for C73R and a second variant that expresses little residual activity, such as P53L, also results in a severe or moderately severe phenotype. Patients heteroallelic for variants that express more residual activity, such as V82F (35 percent of normal activity), A104V (7.7 percent of normal activity), and A66V (14.5 percent of normal activity) have milder forms of CEP, even if the other allele is C73R or another variant that expresses little or no detectable activity. For example, a teenage boy whose genotype was C73R/A66V had only mild cutaneous involvement [26].

There are notable exceptions in genotype-phenotype correlations that suggest that additional modifying factors play a role in disease severity, as illustrated by the following examples:

In a Palestinian family with five siblings who were all shown to be homozygous for a novel S47P mutation that markedly reduced UROS activity, four were clinically affected and one was completely asymptomatic [27].

In a series of 29 patients with CEP, two unrelated individuals with the same CEP genotype showed markedly different clinical phenotypes [28].

In a study of four Spanish patients who shared the same UROS variants, the individual with the most severe phenotype was found to have an additional gain-of-function mutation in the erythroid-specific form of 5-aminolevulinate synthase 2 (ALAS2), the first enzyme of the heme biosynthetic pathway [29]. This demonstrates that ALAS2 variants can modify the CEP phenotype in addition to causing X-linked protoporphyria. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

EPIDEMIOLOGY — CEP is rare, with only a few hundred cases reported in the literature [28,30,31]. The transmission is autosomal recessive. Individuals with a pathogenic variant affecting only one uroporphyrinogen III synthase (UROS) allele are asymptomatic carriers. Some, but not all, homoallelic cases of CEP are associated with consanguinity [27,32-34]. With rare exception [27], compound heterozygotes and homozygotes for known pathogenic variants in UROS are expected to manifest CEP.

CEP occurs with equal frequency in males and females. It shows no apparent ethnic predisposition and has been described in diverse ethnic groups including Cree Native Americans, Black Africans, Japanese people, and individuals from throughout Europe, the Indian subcontinent, and South America [21,30,35,36].

The age of onset (or, in some cases, correct identification) is usually at birth or in early childhood but ranges from hydrops fetalis in utero to milder late-onset forms presenting in up to the seventh decade of life [28,37,38].

CLINICAL FINDINGS

Overview — Cutaneous phototoxicity and hemolytic anemia are the predominant findings in CEP. Neurovisceral symptoms (abdominal pain, psychiatric manifestations, seizures, neurologic symptoms) are not components of CEP.

A description of clinical findings in this very rare disease is necessarily based on the review of case reports, often lacking important details, as well as a few case series. In these reports, the severity of this disease is highly variable and is explained in part by the severity of the uroporphyrinogen III synthase (UROS) variants found in each case.

The major factors that affect disease severity are the level of residual activity of the UROS enzyme and the consequent levels of excess type 1 porphyrins [26]. Additional factors may include the degree of hemolytic anemia and consequent stimulation of erythropoiesis, and the degree of light exposure and resulting photodamage at any given level of increased porphyrins.

Some individuals with adult onset CEP have mild disease and are more likely to manifest skin-only disease with little or no anemia [28]. These cases are often misdiagnosed as porphyria cutanea tarda (PCT), an adult-onset disease and the most common blistering cutaneous porphyria. (See "Porphyrias: An overview", section on 'Blistering cutaneous porphyrias (exemplified by PCT)'.)

In a retrospective study of 29 patients with CEP, the most common clinical findings and their approximate frequencies were as follows [28]:

Photosensitivity – 100 percent

Red urine – 93 percent

Anemia – 66 percent

Photomutilation – 45 percent

Hypertrichosis – 28 percent

Hepatosplenomegaly – 21 percent

Thrombocytopenia – 21 percent

The age of onset of symptoms in this series was highly variable, ranging from birth (in 38 percent) to 40 years. Most patients, and especially those with more severe disease, presented by early childhood.

The porphyrins that circulate and are excreted in urine and deposited in teeth and bone in patients with CEP will fluoresce when exposed to long wave ultraviolet (UV) light. Thus, urine and teeth will fluoresce when illuminated with a Woods lamp [39]. The finding of excess porphyrins and the porphyrin composition in serum, urine, and/or feces are important in the diagnosis of CEP and in its distinction from other porphyrias. (See 'Diagnosis' below and 'Differential diagnosis' below.)

Cutaneous — In most cases, severe cutaneous photosensitivity begins in early infancy and is manifested by increased friability and blistering of the epidermis on the hands, face, and other sun-exposed areas. The blistering skin manifestations of CEP are similar to those in porphyria cutanea tarda (PCT), as well as variegate porphyria (VP), hereditary coproporphyria (HCP), and hepatoerythropoietic porphyria (HEP), but are in most cases much more severe, reflecting the more marked elevation of circulating porphyrins found in severe cases of CEP. Skin friability makes the skin prone to blistering after minor trauma. These manifestations occur only on sun-exposed areas, most commonly the hands, face, ears, neck, and forearms.

Bullae and vesicles contain serous fluid and are prone to rupture and infection. These areas may crust over and progress to scarring and thickening, with areas of hypo- and hyperpigmentation (picture 1). Photomutilation and deformities, often resulting in bacterial infection, are common in severe cases, with loss of fingers, eyelids, nose, and ears (picture 1). Protection from sunlight and antibiotic treatment when needed are essential to prevent these advanced and largely irreversible consequences. (See 'Skin and eye care' below.)

Other cutaneous findings include hypertrichosis of the face and extremities, and erythematous papules on the face [28]. The incidence of cutaneous malignancies does not appear to be increased, although squamous cell carcinoma has been reported [40]. (See 'Prognosis' below.)

Although skin biopsy cannot be used to make the diagnosis of CEP, it may be done to exclude other photosensitive or bullous skin diseases. The skin histologic findings in CEP are characteristic but not specific, and therefore histology is not very helpful for diagnosis. Biopsy of skin lesions can show subepidermal blisters, atrophy, fibrosis, dermal and perivascular hyaline deposits, and hyalinization of connective tissue [41]. (See 'Diagnosis' below.)

Hematologic — Mild to severe anemia from intravascular hemolysis and ineffective erythropoiesis can be a major feature of CEP, especially in severe cases presenting in infancy and childhood. Severe hemolytic anemia in utero can cause hydrops fetalis and fetal ascites. Hemolytic anemia in neonates may cause neonatal jaundice. Phototherapy for hyperbilirubinemia can accelerate skin damage [42]. Patients with severe disease may be transfusion dependent; in one study of 29 patients with CEP, six were transfusion dependent [28]. Anemia may be absent in mild cases of CEP, reflecting either the absence of hemolysis or an adequate compensatory bone marrow response.

Typical findings on the peripheral blood smear in severe cases with anemia include anisocytosis, poikilocytosis, polychromasia, and basophilic stippling [43]. Nucleated red blood cells may also be seen. Consistent with hemolytic anemia, the reticulocyte count is increased; unconjugated bilirubin may be elevated; haptoglobin may be low or undetectable; and urine and fecal urobilinogen are increased.

Hemolytic anemia is very often accompanied by secondary splenomegaly, which can in turn worsen the anemia, and cause leukopenia and thrombocytopenia (ie, hypersplenism). (See "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

Additional hematologic findings can include the following:

Frequent transfusions to treat anemia or to suppress porphyrin synthesis can produce iron overload. (See 'Anemia' below and "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload'.)

Bone marrow evaluation is not diagnostic, but characteristically shows erythroid hyperplasia, porphyrin fluorescence especially in late normoblasts and early reticulocytes, and variable increases in iron and heme by benzidine staining.

Adult-onset CEP has also been associated with myelodysplastic syndromes (MDS) [37,44]. One heterozygous carrier for CEP developed a mild form of the disease in the absence of a bone marrow disorder, probably due to acquired mosaicism affecting the UROS gene and expansion of the porphyric allele or loss of function of the normal allele, but the tissue location of the presumed cellular clone (bone marrow versus liver) could not be identified [45]. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

Ocular — The eyes are also highly sensitive to photodamage. Ocular involvement may include inflammatory changes (blepharitis, scleritis, conjunctivitis) and scleral involvement, with pink fluorescence of the sclera under UV light [46-49]. Eyelids can be destroyed by photomutilation. Corneal scarring can lead to blindness.

Bones and teeth — Bone loss may result from expansion of the hyperplastic bone marrow [28,32,50,51]. It is not clear if porphyrin deposition in bone causes bone loss. Vitamin D deficiency may also contribute to bone demineralization.

Porphyrins deposited in the teeth produce a reddish brown color in natural light, termed erythrodontia (picture 1); the teeth fluoresce on exposure to long wavelength UV light (picture 2 and picture 3) [52]. Marked thinning of the enamel may also occur [52].

Urine — Excess porphyrins enter the plasma from the bone marrow and possibly from circulating erythrocytes. Urinary porphyrin excretion is markedly increased in severe cases, turning the urine pink or red; reddish brown staining of the diapers is sometimes the first sign of the disease in infants. Compared with a normal urinary porphyrin excretion of less than approximately 0.3 mg per day, patients with severe CEP can excrete up to 50 to 100 mg of urinary porphyrins per day. The excreted porphyrins cause the urine to fluoresce red upon exposure to 400 to 420 nm light (picture 4) [39,53].

Amniotic fluid — Porphyrin secretion into the amniotic fluid can turn the fluid brown, and porphyrins can be assayed from amniocentesis fluid [54].

DIAGNOSIS

Evaluation — CEP is an extremely rare disorder that is often not considered, resulting in delayed diagnosis. In a series of 29 patients, the time from first symptoms to diagnosis ranged from eight days to 48 years (mean 8.1 years) [28]. CEP should be suspected in the setting of severe photosensitivity, often accompanied by hemolytic anemia (algorithm 1). Adults and even children with milder disease can present with skin only disease, characterized by chronic cutaneous blistering in areas of sunlight exposure. (See "Approach to the patient with cutaneous blisters", section on 'Photodistributed' and 'Differential diagnosis' below.)

Tissue biopsy (skin, bone marrow) is not required to make a diagnosis of CEP, and there are no specific diagnostic findings with these procedures. (See 'Cutaneous' above.)

As with other porphyrias, the preferred approach to diagnostic testing is to use a single first-line test for screening, followed by more extensive second-line testing if the screening test is positive (table 1). For porphyrias causing blistering skin lesions, the preferred screening test is measurement of total porphyrins in plasma or urine, with the caveat that porphyrins are often nonspecifically elevated in many other medical conditions, especially in urine. (See 'Differential diagnosis' below.)

A 24-hour urine sample is not required. A random urine sample is preferred, with the result normalized to creatinine. Samples should be protected from light during processing and transit because porphyrins are light-sensitive; however, with the marked elevations in CEP light exposure is very unlikely to obscure the diagnosis.

Plasma porphyrins are often 50-fold increased over the upper limit of normal of approximately 1 mcg/dL. In mild cases, plasma and urine levels may be 10-fold less than in severe cases, and in the range for patients with porphyria cutanea tarda (PCT).

If plasma (or urine) porphyrins are elevated, comprehensive second-line testing is needed to establish the type of porphyria, or to determine whether porphyrin elevation (especially in urine) is due to a non-porphyria condition, such as liver disease.

Second-line biochemical testing should include the following (table 1):

Urine and/or plasma porphyrins should be measured and fractionated to determine amounts of the individual porphyrins. In CEP, there is typically a predominance of uroporphyrin I and coproporphyrin I, although other porphyrins such as hepta-, hexa- and pentacarboxyl porphyrins are also elevated. Urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) are not increased in CEP.

A marked elevation in total erythrocyte porphyrins is always found in CEP and this is important to confirm. Fractionation of erythrocyte porphyrins usually shows a predominance of uroporphyrin I and coproporphyrin I. However, especially in milder cases, the marked increase in erythrocyte porphyrins may be mostly due to zinc protoporphyrin, as is found in all other autosomal recessive porphyrias, with the exception of the protoporphyrias (erythropoietic protoporphyria [EPP] and X-linked protoporphyria [XLP]), in which the excess protoporphyrin is predominantly metal-free.

Fecal porphyrin excretion is markedly increased in patients with CEP, typically with a distinctive predominance of coproporphyrin I. There is less increase in uroporphyrin I because it is excreted in urine, whereas coproporphyrin is excreted both by the kidney and liver.

If second-line biochemical testing confirms a diagnosis of CEP, DNA studies are important to identify the underlying familial disease variants. In a new family, the UROS gene can be sequenced, and in a family with known variants, presence of the specific variants can be assayed. This not only provides additional confirmation but enables genetic counseling and screening of family members. There are so many labs offering DNA testing now, that I don’t think we need to make specific recommendations.

Testing for CEP can be initiated before birth by measuring total porphyrins in amniotic fluid or fetal blood [54]. Pathogenic variants in the UROS gene can also be confirmed using fetal cells obtained by amniocentesis or chorionic villous sampling [55,56]. Diagnosis of CEP in utero is important for genetic counseling and appropriate avoidance of light exposure after delivery, especially the harmful photosensitizing effects of photodynamic therapy for neonatal hyperbilirubinemia [42]. (See 'Prenatal counseling' below and 'Skin and eye care' below.)

Diagnostic criteria — The diagnosis of CEP is confirmed by the presence of excess porphyrins in erythrocytes, plasma, and urine with a predominance of uroporphyrin I and coproporphyrin I. An elevation of fecal porphyrins with a predominance of coproporphyrin I is also distinctive. The diagnosis should be confirmed by detection of familial pathogenic UROS gene variants.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of CEP primarily includes the other bullous cutaneous porphyrias: hepatoerythropoietic porphyria (HEP), porphyria cutanea tarda (PCT), variegate porphyria (VP), and hereditary coproporphyria (HCP). All can be readily differentiated from CEP by second-line biochemical testing, and ultimately DNA studies (algorithm 1). (See 'Diagnostic criteria' above.)

Hepatoerythropoietic porphyria (HEP) and porphyria cutanea tarda (PCT) – HEP and PCT, which are due to deficient activity of uroporphyrinogen decarboxylase (UROD), are cutaneous porphyrias with similar skin findings as CEP.

HEP is the homozygous form of familial PCT, most often with onset in early childhood, and can closely resemble CEP clinically with cutaneous manifestations of similar severity. In severe cases of HEP, porphyrin levels may be as high as in CEP. However, a predominance of uroporphyrin and hepta-, hexa-, and pentacarboxyl porphyrin in urine and plasma, as well as zinc protoporphyrin in erythrocytes are biochemical features of HEP that distinguish it from CEP. HEP should then be confirmed by DNA studies to identify UROD mutations.

Mild and adult-onset cases of CEP are often initially misdiagnosed as PCT, a much more common condition [45]. PCT is usually due to an acquired hepatic deficiency of UROD, with porphyrin patterns as in HEP, except that erythrocyte porphyrins are not significantly elevated. Some patients with PCT (approximately 20 percent) are heterozygous for UROD variants, which is an inherited predisposing factor. Plasma porphyrin levels in PCT associated with end stage kidney disease can be much higher than in PCT with normal kidney function, and can be associated with more severe blistering, infection, and even mutilation. PCT is readily distinguished from CEP biochemically by the erythrocyte porphyrin level; erythrocyte porphyrins are markedly elevated in CEP and typically normal or modestly elevated in PCT. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

Variegate porphyria (VP) – VP is a cutaneous porphyria that may be readily confused with mild CEP. Unlike CEP, VP is also one of the acute porphyrias and can cause acute neurovisceral manifestations. VP is autosomal dominant with incomplete penetrance, and results from deficiency of the enzyme protoporphyrinogen oxidase (PPOX). Characteristic biochemical findings include elevations in urinary ALA, PBG, and coproporphyrin III; fecal coproporphyrin III and protoporphyrin; and plasma porphyrins with a characteristic fluorescence peak (at a wavelength of approximately 626 nm) that distinguishes it from all other porphyrias. Erythrocyte porphyrins are normal or only modestly elevated in VP. (See "Variegate porphyria".)

Hereditary coproporphyria (HCP) – HCP usually presents with neurovisceral manifestations, and less commonly with blistering skin lesions. HCP has autosomal dominant transmission with variable penetrance; it results from deficiency of the enzyme coproporphyrinogen oxidase (CPOX). Biochemical findings include increased urinary ALA, PBG, and coproporphyrin III, and fecal coproporphyrin III. Plasma porphyrins are normal in most cases but are expected to be elevated when skin lesions are present. Erythrocyte porphyrins are normal or only modestly elevated. (See "Hereditary coproporphyria".)

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) – EPP is a cutaneous porphyria that is much more common than CEP, but the cutaneous manifestations of these protoporphyrias differ greatly from CEP and the other types of cutaneous porphyria. Patients with EPP experience skin tingling, burning, and significant pain often starting within minutes after sun exposure. Symptoms worsen with more prolonged light exposure and may persist for hours or days but are seldom followed by significant blistering, scarring, or deformity. EPP is autosomal recessive, due to a deficiency of ferrochelatase. X-linked protoporphyria (XLP) has the same phenotype but is due to gain of function variants in the gene encoding the erythroid form of delta-aminolevulinic acid synthase (ALAS2). In EPP and most cases of XLP, erythrocyte porphyrins are predominantly metal-free protoporphyrin. Urine porphyrins are not increased in EPP and XLP, since protoporphyrin is excreted only by the liver. EPP and XLP cases should be confirmed by DNA studies as well. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

Secondary porphyrinuria – The finding of elevations in urinary porphyrins, especially coproporphyrin, in the absence of other findings, such as elevations in plasma or erythrocyte porphyrins or urinary ALA and PBG, is a very nonspecific finding and does not support a diagnosis of any type of porphyria. This may indicate liver disease or lead poisoning, and may also occur due to alcohol use, ingestion of other drugs, or toxins. These effects have been little studied, so isolated porphyrinuria is generally not a suitable focus for further diagnostic evaluation.

Bullous skin disorders – A variety of skin disorders can present with photosensitivity and/or skin fragility that can lead to scarring. These disorders, which do not raise porphyrin levels in urine, plasma, or erythrocytes, are discussed separately. (See "Diagnosis of epidermolysis bullosa", section on 'Skin biopsy' and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Hydroa vacciniforme' and "Xeroderma pigmentosum" and "Diagnosis of epidermolysis bullosa", section on 'When to suspect epidermolysis bullosa'.)

Lead poisoning – Elevated porphyrins can be a nonspecific finding seen in a number of disorders such as lead poisoning. In lead poisoning, erythrocyte zinc protoporphyrin is elevated, and testing for blood lead levels will be diagnostic. (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Lead exposure, toxicity, and poisoning in adults".)

MANAGEMENT

Overview — The mainstay of treatment, especially in severe cases with the highest levels of circulating porphyrins, is avoidance of sunlight exposure to the skin and eyes.

Skin infections should be prevented but treated promptly if and when they occur. Anemia may require red blood cell transfusions; however, this may lead to iron overload and need for iron chelation. Management of individuals with CEP is best achieved by a multidisciplinary team of clinicians (hematologist, dermatologist, ophthalmologist, dentist, and possibly plastic surgeon) [57].

Allogeneic hematopoietic stem cell transplantation is the most effective treatment and should be strongly considered in children with the most severe manifestations. Although circulating porphyrin levels may not be completely normalized, they are greatly reduced, anemia is corrected, and severe skin damage and mutilation are prevented.

Afamelanotide increases light tolerance in erythropoietic protoporphyria (EPP); it has not been studied in CEP and is unlikely to prevent severe and irreversible skin damage. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

Patients with confirmed CEP do not need to avoid medications and steroid hormone preparations that provoke neurovisceral attacks in patients with the acute hepatic porphyrias, since these agents affect the liver and not the bone marrow. Porphyrin levels in CEP would likely be increased by agents such as erythropoietin that stimulate erythropoiesis.

Skin and eye care — Protection of the skin and eyes from sunlight and minor trauma is essential in patients with CEP. These patients may not experience the acute cutaneous pain after sunlight exposure that characterizes erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP), and therefore they are less likely to spontaneously avoid sunlight.

Individuals with severe photodamage of the hands and face do not experience photodamage on light-protected areas, such as the trunk, legs, and feet [57], which supports the effectiveness of avoiding sunlight. However, this requires major restrictions in lifestyle and is especially difficult for children.

Specialized clothing for skin protection for individuals with CEP and other photosensitizing conditions can be purchased and worn when outdoors. Standard window glass, including automobile window glass, does not filter out damaging wavelengths of light, so protective garments including gloves should be worn while driving or riding in automobiles. Avoidance of fluorescent indoor lighting and operating room/surgical theater lights and even incandescent lighting as much as possible is also suggested.

Reflecting sunscreens that protect the skin from all forms of light may be somewhat effective but are often not cosmetically acceptable. Sunscreens that block UVA may also be of some benefit [58]. In one series of seven patients who used reflective sunscreens, five reported subjective benefit, one was unsure, and one found it cosmetically unacceptable [57]. Additional information about sunscreen products is presented separately. (See "Selection of sunscreen and sun-protective measures".)

Therapeutic doses of pharmaceutical-grade beta carotene (Lumitene) are seldom beneficial and should not be used in a manner that would encourage more sunlight exposure. Some clinicians have used oral beta-carotene as a photoprotective agent, based on its use in EPP [58,59]. However, in a series of 29 patients with CEP, 12 received beta-carotene, and only two reported an increased tolerance to light exposure [57]. (See "Overview of vitamin A" and "Beta-carotene: Drug information".)

However, advising patients to avoid sunlight remains the hallmark of managing CEP, and the use of partially effective measures such as these may encourage more light exposure that ultimately causes irreversible skin damage. Protective sunglasses and regularly scheduled ophthalmology examinations are extremely important.

Affected skin should be protected as much as possible from infection. Any bacterial infection of the skin should be recognized promptly and treated with an antibiotic to avoid scarring and mutilation. Loss of digits may result in part from skin infection that was incompletely treated, leading to osteomyelitis. (See "Acute cellulitis and erysipelas in adults: Treatment".)

Bacterial infections that complicate cutaneous blisters (cellulitis, bacteremia, and osteomyelitis) may require intravenous antibiotics. Surgical intervention may be necessary in some cases. In a series of 29 patients, seven required surgical intervention (eg, skin grafting) for severe skin damage [57]. Six of these healed well, and one required amputation of a hand due to delayed wound healing and chronic cellulitis. (See "Acute cellulitis and erysipelas in adults: Treatment".)

Vitamin D — Vitamin D is uniformly deficient in patients with CEP due to sun avoidance, and this should be routinely supplemented [28]. Bone loss may also be due to bone marrow expansion, and it is not clear if therapy with bisphosphonates is helpful. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Vitamin D insufficiency and deficiency in children and adolescents".)

Dental care — Dental care involves a program of careful dental hygiene; cosmetic management may also be indicated [52].

Anesthetic and operative considerations — Patients with CEP undergoing surgery, especially if prolonged, should have special attention paid to avoidance of operating room and recovery room lights, which can cause photodamage [60]. Filters that attenuate damaging wavelengths of light should be used on operating room lights. Anesthetic agents such as barbiturates are dangerous to use in acute hepatic porphyrias and are not of concern in CEP. However, we generally avoid these agents due to lack of reports of their safety [61].

Anemia — Anemia should be evaluated carefully to identify and correct contributing factors such as iron, vitamin B12, or folate deficiencies. Severe cases may be transfusion dependent, and red blood cell (RBC) transfusion may be used to improve anemia and also to reduce the production of excess porphyrins by the bone marrow [32]. For the latter indication, target hematocrits of 32 to 39 percent have been proposed [57,62]. If this strategy is used, however, serial measurements of porphyrins in plasma, erythrocytes, and urine are indicated to objectively assess the therapeutic benefit. Hydroxyurea was reported to further reduce erythropoiesis and bone marrow porphyrin production in a teenager with CEP who was receiving chronic RBC transfusions [62]. Improvement in photosensitivity was noted, although the patient’s transfusion requirement was not reduced.

In a series of 29 patients, seven were treated with chronic hypertransfusion therapy to suppress hematopoiesis, reduce porphyrin production, and improve photosensitivity; six also had symptomatic anemia [57]. Six of the patients received concomitant iron chelation therapy. Three reported improvement in skin symptoms, but effects on porphyrin levels were not described. (See "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload' and "Iron chelators: Choice of agent, dosing, and adverse effects".)

Other interventions have been tried in CEP but are not often used. These include:

Heme therapy, which is effective for treatment of the acute hepatic porphyrias, may be somewhat effective in CEP, but it has not been extensively studied [63,64]. It seems unlikely to be able to provide long term benefit.

Chloroquine has not been beneficial [65-67]. Chloroquine and hydroxychloroquine are only effective in porphyria cutanea tarda (PCT).

Splenectomy may reduce transfusion requirements in some patients with hypersplenism and excessive trapping and destruction of circulating RBCs [32]. Splenectomy may also be beneficial in treating thrombocytopenia due to hypersplenism [68,69]. The effects of such an intervention should be monitored by serial measurements of porphyrin levels in plasma, erythrocytes, and urine. Patients undergoing splenectomy may also have benefitted from concurrent RBC transfusions.

Oral charcoal may increase fecal loss of porphyrins and may be useful for patients who are not transfusion-dependent and have milder disease [70]. It is less successful in more severe cases, and was associated with an apparent exacerbation in one case [71,72]. If used, the effects of treatment on porphyrin levels should be closely monitored.

Iron chelation and phlebotomy — Iron upregulates ALAS2, the initial enzyme in the heme biosynthetic pathway during hemoglobin synthesis, and therefore iron deficiency or removal might decrease porphyrin overproduction in CEP.

One patient with CEP experienced spontaneous improvement in photosensitivity and hemolysis after developing iron deficiency from gastrointestinal bleeding; the patient experienced spontaneous worsening of CEP symptoms when the bleeding stopped [73]. Subsequent treatment with an iron chelating agent improved symptoms and reduced total urine porphyrins from >100,000 to <6000 mcg/24 hours.

Iron depletion by phlebotomy improved hemolysis and photosensitivity and markedly reduced levels of plasma and urine porphyrins in several additional patients with CEP [74,75]. These early results suggest a new approach to treatment of CEP, but because iron deficiency might also have adverse effects, further careful study in additional patients is needed.

Hematopoietic stem cell transplant and gene therapy — Allogeneic hematopoietic stem cell transplant (HCT) has been used as curative treatment in patients with CEP who have severe disease [57,76]. Risks of chemotherapy toxicity, immunosuppression, and graft-versus-host disease may be outweighed in patients with significant morbidity or expected morbidity from CEP, especially if a suitable donor is available. This approach has only been used in children with CEP; the oldest recipient was a 15-year-old who died of post-transplant sepsis [77].

Descriptions of the success of allogeneic HCT for CEP are limited to approximately 20 to 30 cases [78,79]. Six of 29 patients in one series were treated with HCT from a related donor [57]. The mean age at transplant was five to six years, and the main indications for transplant were transfusion-dependent anemia in early childhood, genotypes associated with severe phenotypes, and high risk for photomutilation. Five patients remained essentially cured of their CEP for a mean duration of six years; the sixth (the oldest, at 12 years) experienced progressive CEP symptoms. All experienced transplant complications.

HCT from an unrelated donor is also an option for patients with severe CEP [79]. Two children who received matched unrelated donor HCT were alive and disease-free two and three years following transplant [80]. In another study involving six cases of childhood CEP, survival for 3 to 24 years was reported in four [78]. However, unexpected liver damage was common and deserves further study.

Gene therapy and drugs that affect protein folding — CEP could potentially be treated by gene therapy. Overexpression of the UROS gene has been achieved in cultured hematopoietic cells and induced pluripotent stem (iPS) cells; use of this approach in patients with CEP remains hypothetical [81,82].

Some UROS variants alter protein folding, leading to premature enzyme degradation. Molecular chaperones and proteasome inhibitors have potential for treatment of CEP in the future.

Ciclopirox, a topical antifungal agent, binds to and stabilizes UROS, and administration of ciclopirox restored enzyme activity in a mouse model of CEP with certain UROS missense mutations. If a safe and bioavailable formulation of this drug can be developed and is effective in human CEP, its use will be guided by UROS genotyping [83].

Proteasome inhibitors were shown to partially correct CEP in mice with certain UROS mutations [25].

Prenatal counseling — CEP is an autosomal recessive disorder. Siblings of an affected individual have a 50 percent chance of being a CEP carrier (being heterozygous for a pathogenic variant in UROS) and a 25 percent chance of inheriting a pathogenic variant in the UROS gene from both parents and hence being affected by the disease.

Families should be counseled regarding these risks and available options to reduce them, as well as the importance of prenatal diagnosis for managing affected infants. (See 'Evaluation' above.)

Individuals with CEP can have children. Successful pregnancy was reported in a patient with CEP and a moderate clinical phenotype [84]. The father did not carry a UROS variant. The infant had brown staining of the teeth due to prenatal exposure to maternal porphyrins and subsequently had normal development without evidence of disease. This child was an obligate carrier of a CEP disease variant.

PROGNOSIS — Prognosis is variable depending on the disease severity and the underlying pathogenic variants. Despite disfiguring skin and eye changes, most patients survive into adulthood, with a mean life expectancy of 40 to 60 years [30]. (See 'Genotype phenotype correlations' above.)

In a series of 29 patients in the United Kingdom and Europe, the two most important prognostic factors were age at diagnosis and hematologic manifestations [28]. Early onset disease and severe anemia characterize the most severe cases, and these two features tended to cosegregate; patients diagnosed at an earlier age were more likely to have severe hemolytic anemia. Early onset cases with anemia also have the most severe skin findings, reflecting markedly elevated porphyrin levels. Patients diagnosed before age five had the most severe anemia and the worst prognosis overall. Treatment of the anemia (hypertransfusion, splenectomy, hematopoietic cell transplant) may be beneficial but can also contribute to a poor prognosis. Outcomes in children after hematopoietic stem cell transplantation are more favorable (see 'Hematopoietic stem cell transplant and gene therapy' above). No patient developed a hematologic malignancy. Data from this series are consistent with case reports of patients with adult onset disease that describe mild symptoms and skin-only disease [3,28,38,63,85].

Patients with CEP may experience improvements in skin symptoms during the winter months, when sun exposure is reduced. In one series, some perceived their skin manifestations to improve over their lifetime (17 of 29 patients), while others perceived skin symptoms to worsen (12 of 29 patients) [28]. One patient is reported to have developed a skin malignancy [40]. Protection from sunlight reduced the severity of cutaneous mutilation [28]; however, skin damage from sun exposure, which may be complicated by infection and progressive scarring and mutilation, is often irreversible even when sun exposure is avoided later. Therefore, continuous sun protection is important for maintaining a good prognosis. (See 'Skin and eye care' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Porphyria" and "Society guideline links: Photosensitivity disorders (photodermatoses)".)

SUMMARY AND RECOMMENDATIONS

Genetics – Congenital erythropoietic porphyria (CEP) is a rare, autosomal recessive porphyria that results from severely reduced activity of the heme biosynthetic enzyme uroporphyrinogen III synthase (UROS). (See 'Introduction' above and 'UROS gene variants' above.)

Pathogenesis – Reduced UROS activity during hemoglobin synthesis causes erythrocytic cells to accumulate high levels of nonphysiologic porphyrins that are released into the circulation, deposited in bones and teeth, and excreted in urine and feces. These porphyrins also circulate to the skin where they are activated by light, generating reactive oxygen species that cause severe photodamage. Ineffective erythropoiesis and intravascular hemolysis due to excess porphyrins in circulating erythrocytes causes anemia, especially in patients with severe genotypes. (See 'Enzymatic defect' above.)

Prevalence – CEP can be diagnosed at any age; there is no sex or ethnic predisposition. (See 'Epidemiology' above.)

Clinical findings – CEP should be suspected in individuals with bullous skin disease in sun-exposed areas, including blistering, hypertrichosis, infection, scarring, and mutilation (algorithm 1). Hemolytic anemia, red/brown urine, and red/brown staining of the teeth may also occur. The severity ranges from hydrops fetalis or severe anemia and photosensitivity soon after birth (most common) to skin-only manifestations that develop in adulthood, often in the setting of a myeloproliferative disorder. Acute neurovisceral attacks are not a feature of CEP. (See 'Clinical findings' above.)

Evaluation – The evaluation includes first-line testing for elevation of porphyrins in plasma or urine (table 1). A positive finding should be followed by comprehensive porphyrin analysis, especially including red blood cell (RBC) porphyrins. The diagnosis is confirmed by demonstration of elevated uroporphyrin I and coproporphyrin I in plasma (or serum), urine, and RBCs, and coproporphyrin I in stool, followed by DNA studies to identify familial UROS gene variants. Diagnosis can be made in utero. (See 'Diagnosis' above.)

Differential – CEP can be distinguished from other bullous cutaneous porphyrias by the pattern of excess porphyrins in urine, plasma, erythrocytes, and stool. (See 'Differential diagnosis' above and "Porphyrias: An overview".)

Management – Management requires a multidisciplinary approach (see 'Management' above):

Protection of skin and eyes from light exposure, meticulous skin care, and prompt treatment of bacterial infections are essential. Patients seldom have acute symptoms during sun exposure and may not realize the ultimate harm (permanent skin damage and photomutilation) caused by sunlight.

Regular ophthalmologic and dental care and vitamin D supplementation are required.

Behavioral modifications (eg, sun avoidance) are important and can be especially difficult in children.

RBC transfusions are appropriate for severe anemia and to suppress hematopoiesis and porphyrin production in patients with severe skin symptoms.

Quality of life and reproductive planning deserve ongoing attention.

Allogeneic hematopoietic stem cell transplant is the only curative treatment. Transplant deserves consideration, especially in children with severe disease.

Iron chelation and phlebotomy have reduced porphyrin levels and improved symptoms in some cases; these approaches deserve further study.

Other treatments may be of some value, but none of these lessens the importance of avoiding sunlight.

Prognosis – More severe disease with onset in utero or during infancy/childhood and a worse prognosis is seen with more severe pathogenic variants in UROS.(See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.

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References

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