Congenital erythropoietic porphyria

Congenital erythropoietic porphyria (CEP) also called Gunther’s disease is an extremely rare inherited autosomal recessive disorder that involve defects in heme or ‘haem’ biosynthetic pathway caused by mutations (changes) in the UROS gene which results in low levels of the enzyme uroporphyrinogen III cosynthase or uroporphyrinogen-III synthase (UROS), the fourth enzyme in the heme biosynthetic pathway ¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰. The UROS (uroporphyrinogen III synthase or uroporphyrinogen III cosynthase) enzyme is involved in the production of a molecule called heme (haem). Heme is vital for all of the body’s organs, although it is most abundant in the blood, bone marrow, and liver. Heme is an essential component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). The production of heme is a multi-step process that requires 8 different enzymes. In the presence of insufficient uroporphyrinogen III synthase (UROS) activity, hydroxymethylbilane (HMB), the product of the third step spontaneously closes and forms the non-physiological compound uroporphyrinogen I, which is then acted upon by uroporphyrinogen decarboxylase (UROD) the fifth enzyme in the heme synthetic pathway to form coproporphyrinogen I ²¹. Coproporphyrinogen I then oxidizes spontaneously to form coproporphyrin I and uroporphyrin I, two harmful and non-physiological compounds associated with abnormalities involving various organs ¹. In congenital erythropoietic porphyria (CEP), these toxic porphyrins mostly accumulate in red blood cell precursors (erythroblasts) in your bone marrow, as well as your teeth, bones, urine, and feces. These toxic porphyrins are not significantly elevated in your liver. Your bone marrow, the spongy tissue inside your bones, is essential for producing blood cells and supporting the immune system. Your bone marrow acts as a factory for red blood cells, white blood cells, and platelets, which are vital for oxygen transport, fighting infection, and blood clotting, respectively. Your bone marrow also plays a role in storing fat and supporting bone and cartilage health. As these toxic porphyrins accumulate in your bone marrow, they may be released into your blood and subsequently found in the plasma and mature red blood cells. They then may travel to your skin, and upon exposure to light, generate free radicals that can damage cells and tissues. This leads to disease characterized by severe skin photosensitivity and breakdown of red blood cells (hemolysis) ²². The major symptom of congenital erythropoietic porphyria (CEP) is hypersensitivity of your skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the photo-activated porphyrins in your skin cause skin friability and blistering (bullae) and the fluid-filled sacs may rupture and the lesions often get infected. These infected lesions can lead to scarring, bone loss, and in severe instances, this can lead to skin mutilation and deformities ²³. Your face, ears, neck, arms, forearms and hands are the most commonly affected areas.

Footnotes: An illustration of the heme biosynthesis pathway and congenital erythropoietic porphyria (CEP) pathophysiology. Each number represents the enzyme of the corresponding step: (1) aminolevulinic acid synthase (ALAS), (2) aminolevulinic acid dehydratase (ALAD), (3) hydroxymethylbilane synthase (HMBS), (4) uroporphyrinogen III synthase (UROS), (5) uroporphyrinogen decarboxylase (UROD), (6) coproporphyrinogen-III oxidase (CPOX), (7) protoporphyrinogen oxidase (PPOX), (8) ferrochelatase (FECH). The gray–white rectangle represents the clinical spectrum that narrows by the increase in the age of onset, where the gray beginning expresses the concurrence of black-and-white-indexed involvements.

Figure 2. Congenital erythropoietic porphyria (CEP)

Footnotes: Congenital erythropoietic porphyria (CEP) in a 13-year-old female. (A) a dyspigmented sclerodermatous appearance of the face accompanied with linear and spotted atrophic lesions. (B) Immense areas of ulceration over the dorsum of the hand, with acrolysis of the bones and soft tissues at the ends of the fingers. (C) Healing ulcers on the face and dorsum of the hand after 1 month of treatment; the skin improved in terms of pigmentation and elasticity, with no active ulcers.

Figure 3. Congenital erythropoietic porphyria (CEP) signs

Footnotes: (A) The mutilated nose bridge; (B) Porphyrins accumulation on the gums and erythrodontia; (C) Hands with infected bullae and mutilated index fingers; (D) hypertrophied scars in sun-exposed dorsal foot areas and verrucous growth over the toes

Figure 4. Congenital erythropoietic porphyria under Wood’s lamp

Footnotes: (A) Wood’s lamp examination of the face, (B) Wood’s lamp examination of the hands, (C) Wood’s lamp examination of the feet, showing red-pink fluorescence from teeth and blue hue from sun-exposed skin areas.

Figure 5. Congenital erythropoietic porphyria urine

Figure 6. Porphyrin molecular structure

Footnote: Molecular structure of porphyrin (M represent metal ions, such as Mg, Cu, Fe, Zn, etc.).

Figure 7. Hemoglobin molecular structure

Figure 8. Heme biosynthesis pathway

Footnotes: The heme biosynthetic pathway requires 8 enzymatic steps. Heme synthesis pathway showing the enzymes involved in the heme synthesis pathway and the associated porphyrias with the disruption of each specific enzyme. Gain-of-function variants in ALAS2 result in X-linked protoporphyria (XLP), and loss-of-functions variants in FECH result in erythropoietic protoporphyria (EPP). In both X-linked protoporphyria (XLP) and erythropoietic protoporphyria (EPP), metal-free protoporphyrin IX (PPIX) accumulates in erythroblasts, erythrocytes, the plasma, and the biliary system. Metal-free protoporphyrin IX (PPIX) is photosensitive, particularly to visible light in the blue range, and the light-mediated activation of metal-free protoporphyrin IX (PPIX) produces free radicals that damage the surrounding tissues.

Enzymes, encoded by genes, catalyze each of the steps. Gene mutations cause deficient enzyme production. Disruptions are indicated by red lines connecting enzymes with the resultant porphyrias. ALAS (ALAS2) = aminolevulinate synthase (aminolevulinate synthase 2); ALAD = delta-aminolevulinic acid dehydratase; PBGD = porphobilinogen dehydratase; HMBS = hydroxymethylbilane synthase; UROS = uroporphyrinogen-III synthase; UROD = uroporphyrinogen III decarboxylase; CPOX = coproporphyrinogen-III oxidase; PPOX = protoporphyrinogen oxidase; FECH = ferrochelatase.

Porphyrias resulting from disruption of enzyme production. XLP (X-linked protoporphyria); ADP (aminolevulinic acid dehydratase porphyria); AIP (acute intermittent porphyria); CEP (congenital erythropoietic porphyria); PCT (porphyria cutanea tarda); HCP (hereditary coproporphyria); VP (variegate porphyria); EPP (erythropoietic protoporphyria).

Abbreviations: ALA = aminolevulinic acid; PBG = porphobilinogen; HMB = hydroxymethylbilane; URO III = uroporphyrinogen III; COPRO III = coproporphyrinogen III; PROTO’gen IX protoporphyrinogen IX; PPIX = protoporphyrin IX; Fe2+ = iron.

Figure 9. Uroporphyrinogen III synthase (UROS) enzyme activity

Footnotes: UROS (uroporphyrinogen III synthase) enzyme catalyzes the cyclization of hydroxymethylbilane (HMB) with concomitant inversion of ring D to yield uroporphyrinogen III (URO III) ²⁹. Deficiency of UROS (uroporphyrinogen III synthase) enzyme results in accumulation of HMB (hydroxymethylbilane), most of which is converted nonenzymatically to non-physiological compound uroporphyrinogen I, which is then acted upon by uroporphyrinogen decarboxylase (UROD) the fifth enzyme in the heme synthetic pathway to form coproporphyrinogen I ²¹. Coproporphyrinogen I then oxidizes spontaneously to form the porphyrins coproporphyrin I and uroporphyrin I. In congenital erythropoietic porphyria (CEP), these toxic porphyrins mostly accumulate in red blood cell precursors in your bone marrow, as well as your teeth, bones, urine, and feces. These toxic porphyrins are not significantly elevated in your liver. This leads to disease characterized by severe skin photosensitivity and breakdown of red blood cells (hemolysis) ²².

Figure 10. Congenital erythropoietic porphyria pathophysiology

Foootnotes: (A) Heme biosynthetic pathway and the porphyrias resulting from the indicated heme biosynthetic enzyme defect. There are 8 enzymatic steps in the conversion of glycine and succinyl-CoA to heme. The heme biosynthetic enzymes are italicized, their substrates and products are indicated, and the resulting porphyrias are shown in boxes. Note that there are two aminolevulinic acid synthase (ALAS) isozymes: a housekeeping enzyme, ALAS1, encoded by a gene that is regulated by negative feedback repression by heme, and an erythroid specific enzyme, ALAS2, that is regulated by the iron response proteins and erythroid transcription binding proteins.

(B) Uroporphyrinogen synthase (UROS) normally converts hydroxymethylbilane (HMB) to uroporphyrinogen III. When the UROS activity is markedly decreased, HMB (hydroxymethylbilane) is non-enzymatically converted to uroporphyrinogen I, which is then enzymatically converted to oproporphyrinogen I by uroporphyrinogen decarboxylase (UROD). The accumulated uroporphyrinogen I and coproporphyrinogen I are oxidized to their respective porphyrins, which are photoactive and cause the sun/light-induced hemolysis and cutaneous manifestations of congenital erythropoietic porphyria (CEP).

Congenital erythropoietic porphyria cause

Congenital erythropoietic porphyria is caused by mutations in the UROS gene located on chromosome 10q26.2 ²⁵. Congenital erythropoietic porphyria (CEP) is rarely inherited in X-linked inheritance pattern due to mutation of the GATA1 gene located on the X chromosome (chromosome Xp11.23) that affected males only while the female heterozygotes were mostly asymptomatic ²⁶, ¹⁵, ²⁷, ²². Females who are heterozygous for GATA1 gene will be either asymptomatic or have a milder disease with predominantly hematologic abnormalities due to skewed X-chromosome inactivation ¹⁵, ²⁷. In a small percentage of congenital erythropoietic porphyria patients (>10%), a disease-causing mutation has not been detected in the UROS or GATA1 genes, raising the possibility that additional gene(s) may play a role in congenital erythropoietic porphyria pathogenesis ²⁸.

Disease-causing mutations in either UROS gene or GATA1 gene result in absent or markedly reduced UROS (uroporphyrinogen III synthase) enzymatic activity. UROS (uroporphyrinogen III synthase) enzyme catalyzes the cyclization of hydroxymethylbilane (HMB) with concomitant inversion of ring D to yield uroporphyrinogen III (URO III) ²⁹. Deficiency of UROS (uroporphyrinogen III synthase) enzyme results in accumulation of HMB (hydroxymethylbilane), most of which is converted nonenzymatically to non-physiological compound uroporphyrinogen I, which is then acted upon by uroporphyrinogen decarboxylase (UROD) the fifth enzyme in the heme synthetic pathway to form coproporphyrinogen I ²¹. Coproporphyrinogen I then oxidizes spontaneously to form the porphyrins coproporphyrin I and uroporphyrin I. In congenital erythropoietic porphyria (CEP), these toxic porphyrins mostly accumulate in red blood cell precursors in your bone marrow, as well as your teeth, bones, urine, and feces. These toxic porphyrins are not significantly elevated in your liver. Since these toxic porphyrins are photocatalytic compounds, exposure of the skin to sunlight and other sources of long-wave ultraviolet light elicits a phototoxic reaction, resulting in blistering and vesicle formation as well as increased friability of the skin and breakdown of red blood cells (hemolysis) ²², ³⁰, ³¹.

Congenital erythropoietic porphyria inheritance pattern

Congenital erythropoietic porphyria (CEP) is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. Patients with congenital erythropoietic porphyria (CEP) are either homozygotes or compound heterozygotes for mutations of the UROS gene at 10q25.2-q26.3 that encodes uroporphyrinogen III synthase (UROS), a cytosolic enzyme that converts hydroxymethyl bilane (HMB) to uroporphyrinogen III. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, and usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Congenital erythropoietic porphyria (CEP) is rarely inherited in X-linked inheritance pattern due to mutation of the GATA1 gene located on the X chromosome that affected males, while the female heterozygotes were mostly asymptomatic ¹⁵, ²⁷, ²². Females who are heterozygous for GATA1 gene will be either asymptomatic or have a milder disease with predominantly hematologic abnormalities due to skewed X-chromosome inactivation ¹⁵, ²⁷.

Genetic counseling is recommended for affected individuals and their families.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://clinics.acmg.net/) has a searchable database of medical genetics clinic services in the United States.

Figure 11. Congenital erythropoietic porphyria (CEP) autosomal recessive inheritance pattern

Congenital erythropoietic porphyria pathophysiology

The pathogenesis of congenital erythropoietic porphyria is explained by markedly deficient, but not absent uroporphyrinogen III synthase (UROS) activity. Consistent with its autosomal recessive inheritance, a very low level (≤1% of normal) appears to be sufficient for life. A uroporphyrinogen III synthase (UROS) knockout mouse model was lethal in the early embryo, indicating that the absence of UROS activity is not compatible with life ⁵¹. Deficient UROS activity leads to the accumulation of the enzyme’s substrate, hydroxymethylbilane (HMB), most of which is converted non-enzymatically to uroporphyrinogen I ¹⁶. Although uroporphyrinogen I can undergo decarboxylation by uroporphyrinogen decarboxylase (UROD) to form hepta-, hexa- and pentacarboxyl-porphyrinogen I, and, finally, coproporphyrinogen I, further metabolism cannot proceed because the next enzyme in the pathway, coproporphyrinogen oxidase (CPOX), is stereospecific for the III isomer ¹⁶. The isomer I porphyrins are non-physiologic, phototoxic, cannot be metabolized to heme, and are pathogenic when they accumulate in large amounts ²², ⁵², ⁵³.

Uroporphyrin I accumulation in bone marrow, red blood cells, plasma and urine is the biochemical hallmark of congenital erythropoietic porphyria (CEP). Large amounts of isomer I porphyrinogens in bone marrow erythroid precursors (especially normoblasts and reticulocytes) and red blood cells (erythrocytes) undergo auto-oxidation to the corresponding porphyrins, which damage red blood cells and are deposited in tissues and bones. Photosensitivity occurs because these porphyrins are photocatalytic and cytotoxic compounds ⁵². Exposure of the skin to sunlight and other sources of long-wave ultraviolet (UV) light results in blistering and vesicle formation and increased friability of the skin ³⁰. Damage to the red blood cells (erythrocytes) leads to hemolysis, which is almost always present, but may not be accompanied by anemia if erythroid hyperplasia is sufficient to compensate for the increased rate of erythrocyte destruction ¹⁶. The degree of compensation may vary over time but in severe cases, chronic hemolysis and ineffective erythropoiesis may result in transfusion dependence ²².

Accumulated porphyrins are excreted in large amounts in urine and feces and pink to dark-reddish urine is typically noted in the diaper shortly after birth. Urinary porphyrin concentrations are markedly increased (100–1000 times normal; up to 50–100 mg/day) and consist mostly of the uroporphyrin I and coproporphyrin I isomers, with lesser increases in hepta-, hexa- and pentacarboxylporphyrins I isomers ⁵⁴. Although type I urinary porphyrin isomers predominate, type III isomers also are increased. Fecal porphyrins are also markedly increased with a predominance of coproporphyrin I. Fecal isocoproporphyrins are not increased ⁵⁵. As opposed to the acute hepatic porphyrias, there is no elevation of urinary aminolevulinic acid (ALA) or porphobilinogen (PBG).

Congenital erythropoietic porphyria signs and symptoms

Congenital erythropoietic porphyria or Gunther disease severity and age at onset of symptoms are highly variable between individuals. For many, the onset of symptoms and diagnosis are often in infancy. Some do not develop symptoms until adulthood, their symptoms are usually milder and primarily skin related ⁵⁶.

Congenital erythropoietic porphyria 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 and fluoresces with a Wood’s lamp (ultraviolet light). Congenital erythropoietic porphyria (CEP) or Gunther disease major symptoms are sensitivity of the skin to sunlight and some types of artificial light, and anemia which can be very severe. Skin photosensitivity may be extreme, and can lead to blistering, severe scarring and increased hair growth (hypertrichosis). The fluid-filled blisters may rupture and get infected. These infected wound can lead to scarring, bone loss, and deformities. The hands, arms, and face are the most commonly affected areas. Increased hair growth (hypertrichosis) on sun-exposed skin, brownish-colored teeth (erythrodontia), and reddish-colored urine are common. There may be bone fragility and vitamin deficiencies, especially vitamin D deficiency. Vitamin D is a fat-soluble vitamin that essential for bone development and maintenance, as it enhances calcium, magnesium, and phosphate absorption. Vitamin D deficiency due to sunlight avoidance in people with congenital erythropoietic porphyria can lead to a range of health problems, including bone disorders, muscle weakness, and an increased risk of fractures.

Red blood cells have a shortened life-span, and anemia often results. Synthesis of heme and hemoglobin are actually increased to compensate for the shortened red blood cell survival. The spleen can be enlarged due to extramedullary erythropoiesis, particularly in people with severe hemolytic anemia.

The most common symptom of congenital erythropoietic porphyria (CEP) is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with blistering of the skin occurring after exposure. Affected individuals may also exhibit abnormal accumulations of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). Affected areas of the skin may develop sac-like lesions (vesicles or bullae), scar, and/or become discolored (hyperpigmentation) if exposure to sunlight is prolonged. These affected areas of skin may become abnormally thick. In addition, in some cases, affected individuals may also exhibit malformations of the fingers and nails. The severity and degree of photosensitivity differ depending on the severity of the patient’s gene lesions which correlate with the deficient enzyme activity. In the great majority of congenital erythropoietic porphyria (CEP) cases, photosensitivity is seen from birth; however, in some cases, it may not occur until childhood, adolescence or adulthood. Patients also have brownish discolored teeth (erythrodontia), which fluoresce under ultraviolet light.

In more severe congenital erythropoietic porphyria (CEP) cases, other symptoms can include a low level of red blood cells (anemia), enlargement of the spleen (secondary hypersplenism), and increased hair growth (hypertrichosis) ¹⁶. The anemia can be severe and such patients require periodic blood transfusions to quickly increase the amount of red blood cells and iron in the blood. In severely affected patients, anemia may be present in the fetus (non-immune hydrops fetalis). Eye problems also can occur including corneal scarring, eye inflammation, and infections.

Skin involvement

Skin photosensitivity usually begins shortly after birth and is characterized by increased friability and blistering of the epidermis on the hands and face and other sun-exposed areas. Bullae and vesicles containing serous fluid which fluoresces due to their porphyrin content. Blisters are prone to rupture and become infected. Recurrent vesicle formation and secondary infection can lead to cutaneous scarring and deformities, as well as to loss of digits and facial features such as the eyelids, nose and ears. The skin may be thickened, with areas of hypo- and hyper-pigmentation and hypertrichosis of the face and extremities ⁵⁷. Adult-onset congenital erythropoietic porphyria (CEP) patients have milder clinical symptoms and often exhibit only the skin manifestations of congenital erythropoietic porphyria (CEP) ⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶², ⁶³. Photosensitivity symptoms are provoked mainly by visible light (400–410 nm Soret wavelength) and to a lesser degree by wavelengths in the long-wave UV region. Affected individuals are also sensitive to sunlight that passes through window glass that does not filter long-wave UVA or visible light as well as to light from artificial light sources ⁶⁴.

Hemolytic anemia

Mild to severe hemolysis is accompanied by anisocytosis, poikilocytosis, polychromasia, basophilic stippling, reticulocytosis, increased nucleated red cells, absence of haptoglobin, increased unconjugated bilirubin and increased fecal urobilinogen. Plasma iron turnover also is increased ⁶⁵. Hemolysis presumably results from the accumulated uroporphyrin I in erythrocytes. Secondary splenomegaly develops in response to the increased uptake of abnormal erythrocytes from the circulation, which may contribute to the anemia and also may result in leucopenia and thrombocytopenia. The latter is sometimes associated with significant bleeding and splenectomy may be beneficial in such cases. Anemia due to hemolysis can be severe. Erythroid hyperplasia and markedly ineffective erythropoiesis usually accompany hemolytic anemia in transfusion-dependent patients ⁵⁴, ⁶¹, ⁶⁶.

In the three male patients with congenital erythropoietic porphyria (CEP) due to GATA1 mutations, hematologic abnormalities including dyserythropoietic anemia, beta-thalassemia intermedia, thrombocytopenia, and hereditary persistence of fetal hemoglobin have been described ¹⁵, ²⁷.

Other Clinical Features

Deposition of porphyrins can cause corneal ulcers and scarring, which can ultimately can lead to blindness ¹⁶. Other eye signs and symptoms can include scleral necrosis, necrotizing scleritis, seborrheic blepharitis, keratoconjunctivitis, sclerokeratitis, and ectropion ⁶⁷, ⁶⁸, ⁶⁹. Porphyrins deposited in the teeth produce a reddish-brown color called erythrodontia. The teeth may fluoresce on exposure to long-wave ultraviolet light.

Deposition of porphyrins in bone causes osteopenia (lower than normal bone density) due to demineralization ³⁷, ⁵⁴, ⁷⁰, ⁷¹. The risk for osteopenia and osteoporosis is further increased by vitamin D deficiency, which individuals with congenital erythropoietic porphyria (CEP) are prone to due to avoidance of sun exposure. Porphyrin accumulation in the bone can also cause expansion of the bone marrow, which can lead to hyperplastic bone marrow observed on biopsy ³¹, ⁵⁷.

Congenital erythropoietic porphyria diagnosis

The diagnosis of congenital erythropoietic porphyria may be suspected when the 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 biochemical diagnosis of congenital erythropoietic porphyria is established by detection of markedly elevated levels of uroporphyrin I and coproporphyrin I in urine, red blood cells or amniotic fluid as well as high fecal coproporphyrin I concentrations. Diagnostic confirmation requires the demonstration of the specific UROS enzyme activity and/or by identifying the specific mutation(s) in the UROS gene which is/are responsible for the impaired enzyme ²².

Congenital erythropoietic porphyria should be considered in the differential diagnosis of non-immune hydrops fetalis, in which case the amniotic fluid surrounding the fetus will be pink, dark-red or brown, and should examined for porphyrins ⁷². Newborns with pink to dark-red urine-stained diapers should immediately have diagnostic studies. Congenital erythropoietic porphyria (CEP) also should be considered in children or adults who have porphyrinuria or skin blistering following exposure to sunlight or other sources of long-wave ultraviolet light. In some cases, the disease is less severe and presents in adult life with mild anemia and/or skin lesions.

Congenital erythropoietic porphyria (CEP) should be suspected in individuals with the following clinical and laboratory findings and family history ¹.

• Nonimmune hydrops fetalis
• Signs of congenital erythropoietic porphyria
  • Pink-to-dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
  • Hemolytic anemia
  • Severe cutaneous photosensitivity with onset usually in infancy or early childhood
  • Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
  • Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
  • In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
  • Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
  • Corneal ulcers and scarring
  • Hypertrichosis of the face and extremities
• Laboratory findings include markedly increased levels of uroporphyrin I and coproporphyrin I isomers in red blood cells, urine, or amniotic fluid as well as coproporphyrin I in feces

Prenatal and preimplantation genetic diagnoses are available for subsequent pregnancies in congenital erythropoietic porphyria families.

Congenital erythropoietic porphyria treatment

Avoidance of sun and light exposure, including the long-wave ultraviolet light that passes through window glass or is emitted from artificial light sources is essential to prevent the skin lesions in individuals with congenital erythropoietic porphyria (CEP) ¹. The use of topical sunscreens containing zinc oxide or titanium oxide, protective clothing, long sleeves, hats, gloves, and wraparound sunglasses are strongly recommended. Individuals with congenital erythropoietic porphyria will benefit from window tinting or using vinyls or films to cover the windows in their car or house and the use of reddish incandescent bulbs, filtering screens for fluorescent lights ¹. 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 laws.

Wound care is necessary to prevent infection of opened blisters; surgical intervention may be necessary; blood transfusions with iron chelation are necessary when hemolysis is significant to maintain the hematocrit >35 to decrease reticulocytosis in transfusion-dependent patients ³⁷, ¹. Chronic transfusions have been useful in decreasing the bone marrow production of the phototoxic porphyrins.

Blood transfusions and perhaps removing the spleen may reduce porphyrin production by the bone marrow. Activated charcoal given by mouth is sometimes effective.

When successful, bone marrow transplantation (BMT) or hematopoietic stem cell (HSCT) transplantation has cured patients with congenital erythropoietic porphyria, but is accompanied by specific risks of complications and should be considered in children with severe skin and bone marrow involvement ¹, ³⁸, ³⁹, ⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷.

Evaluations Following Initial Diagnosis

To establish the extent of congenital erythropoietic porphyria disease and needs in an individual diagnosed with congenital erythropoietic porphyria (CEP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Hematologic indices including reticulocytes and bilirubin (to assess hemolysis) and iron profile (to assess iron storage)
• Serum calcium and vitamin D concentrations; bone densitometry
• Liver function tests, especially in transfusion-dependent individuals given the risk for liver disease due to iron storage
• Skin evaluation to assess photosensitivity, photomutilation, and secondary skin changes (thickening, hyper- or hypopigmentation, hypertrichosis)
• Eye evaluation for corneal ulcers and scarring and other ocular manifestations
• Teeth assessment for erythrodontia (reddish-brown color from porphyrin deposition)
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of congenital erythropoietic porphyria (CEP) in order to facilitate medical and personal decision making

Sun Avoidance and Skin Protection

There is no FDA-approved treatment for this disease or specific treatment for the photosensitivity. In patients who have not undergone bone marrow transplantation (BMT) or hematopoietic stem cell (HSCT) transplantation, exposure to sunlight, ultraviolet light as well as light emitted by fluorescent sources, should be avoided. Sunscreen lotions containing zinc oxide or titanium oxide can be beneficial, but do not replace strict avoidance of sun and light exposure ⁷³. Most individuals with congenital erythropoietic porphyria (CEP) try to adjust their daily life in order to reduce light exposure as much as possible, which in some cases includes choosing a profession which allows work during the night. This leads to a very restricted family and social life and quality of life is often significantly decreased.

Skin trauma should be avoided and the use of skin antiseptics should be encouraged to prevent bacterial superinfections that can complicate cutaneous blisters and result in scarring and mutilation. Further measures in an effort to minimize bacterial colonization if affected areas and decrease the risk for cutaneous complications could include bleach baths as well as topical treatment with hypochlorous acid solution ⁷⁴. Severe infections such as cellulitis and bacteremia may have to be treated with intravenous antibiotics and long-term oral antibiotic therapy to suppress chronic skin infections may be required.

Pharmacologic photoprotection has been explored in erythropoietic protoporphyria (EPP), which is the third most common porphyria ⁷⁵. While beta-carotene has been reported to provide some photoprotective effect in erythropoietic protoporphyria (EPP) patients, it has not proven to be beneficial in congenital erythropoietic porphyria (CEP) ⁷⁶, ⁷⁵. Recently, afamelanotide (Scenesse®) – a synthetic melanocortin stimulating hormone analog – was approved for erythropoietic protoporphyria (EPP) patients by the European Medicines Agency in 2014. This hormone is implanted subcutaneously and promotes melanin synthesis via the melanocortin-1 receptor. Beneficial effects have been reported in clinical trials with erythropoietic protoporphyria (EPP) patients ⁷⁷. However the use of afamelanotide (Scenesse®) in congenital erythropoietic porphyria (CEP) patients has not been investigated and it is unclear if the congenital erythropoietic porphyria (CEP) cutaneous complications can be prevented. One recent case report describes an adult patient with severe congenital erythropoietic porphyria (CEP) who underwent treatment with afamelanotide over a period of one year. While improved tolerance of sun exposure was reported by the individual, no protective effect was observed in already scarred areas of hands and face ⁷⁸.

Newborns with a known diagnosis of congenital erythropoietic porphyria (CEP) who develop hyperbilirubinemia should not receive photodynamic therapy to avoid its harmful photosensitizing effects and subsequent severe cutaneous blistering and scarring ⁵⁵.

Hemolytic anemia treatment

In cases of severe hemolysis, frequent blood transfusions may be necessary. Chronic transfusions (every 2–4 weeks) can suppress erythropoiesis and and decrease porphyrin production, which reduces porphyrin levels and photosensitivity ³⁷. Such therapy is likely to be successful if the hematocrit remains above 32% (target hematocrit greater than 35%) and parenteral or oral iron chelators can be administered to reduce the resulting iron overload ⁷⁹. Experimental induction of iron deficiency either using treatment with iron chelators or via phlebotomies (removal of blood) improved photosensitivity and hemolysis in a few affected individuals ⁸⁰, ⁸¹, ¹³, ⁸².

Treatment with hydroxyurea to reduce the bone marrow porphyrin synthesis has been used in some severe congenital erythropoietic porphyria (CEP) cases and may be considered ⁸³. Splenectomy may be considered for patients with splenomegaly and hemolytic anemia, thrombocytopenia and leukopenia. Removing the spleen may correct blood dyscrasia, improve the red blood cell lifespan and substantially reduce transfusion requirements in some patients. It may indirectly also lead to reduced photosensitivity ³⁷.

Efforts to reduce porphyrin levels by administration of hydroxychloroquine, by plasmapheresis, and by intravenous hematin have not shown a clear benefit. Oral charcoal may increase fecal loss of porphyrins ⁸⁴ and may be considered for patients who are not transfusion-dependent and have milder disease. Oral charcoal seems less successful in more severe cases ⁸⁵, ⁸⁶. Iron deficiency induced by treatment with deferasirox led to better erythroid differentiation in the bone marrow and improved hemolysis as well as photosensitivity in one patient ⁸⁰.

Eye treatments

• Avoidance of damage to the eyelids and cornea by wearing wraparound sunglasses
• Topical antibiotics for corneal ulcers, scleritis, and blepharitis
• Artificial tears and lubricants to help prevent dry eyes in those with ectropion
• Corrective surgery of eyelids to help protect the cornea from injury in those with ectropion ⁴⁵

Bone loss treatment

Bisphosphonates can be considered in individuals with osteoporosis ⁴⁵.

Monitoring

Monitor blood indices including iron profile, reticulocyte count, and bilirubin to assess hemolysis every six months. In those receiving blood transfusions, monitor for hemolysis more frequently and for iron overload. Monitor liver function and vitamin D 25-OH every six to twelve months in all affected individuals.

Agents to avoid

All affected individuals should avoid sunlight and UV light. To avoid eye complications and damage to the eyelids, wrap-around sun glasses should be worn. Corneal ulcers, scleritis, and blepharitis should be treated with topical antibiotics. In patients with ectropion, corrective surgery of the eyelid to help protect the cornea from injury may be indicated ⁴⁵. In individuals undergoing surgeries, use of protective filters for artificial lights in the operating room to prevent phototoxic damage ⁸⁷.

To avoid bone demineralization, vitamin D supplementation is indicated and bisphosphonates can be considered in individuals with osteoporosis ⁴⁵.

In those with liver dysfunction avoid drugs that may induce cholestasis (e.g., estrogens).

Pregnancy Management

Successful pregnancies in women with congenital erythropoietic porphyria resulting in healthy and unaffected children have been described ⁸⁸, ³⁶.

Protective filters for artificial lights should be used in the delivery/operating room to prevent phototoxic damage to the mother during delivery ⁸⁷.

Therapies Under Investigation

Although there are no clinical trials at the present time, therapeutic approaches under investigation include phlebotomy or iron chelation strategies to reduce the hemolysis and decrease the accumulated porphyrins and, thus, photosensitivity ⁸⁰, ⁸¹, ¹³, ⁸².

A mice model of congenital erythropoietic porphyria (CEP) is being used to investigate pharmacologic chaperone therapy (i.e., administration of small-molecule drugs to enhance the residual activity of mutated enzymes that have low activities or are unstable). Specifically, use of the antimicrobial agent ciclopirox as a chaperone-stabilized UROIII-synthase and reversed congenital erythropoietic porphyria (CEP)-related findings such as abnormal URO I levels in the blood, splenomegaly, and liver porphyrins ⁸⁹. Studies involving use of this medication in humans have not yet been performed.

Congenital erythropoietic porphyria prognosis

Congenital erythropoietic porphyria or Gunther disease severity and age at onset of symptoms are highly variable between individuals. For many, the onset of symptoms and diagnosis are often in infancy. Some do not develop symptoms until adulthood, their symptoms are usually milder and primarily skin related ⁵⁶. Due to the hematological complications and an increased risk of infection, overall life expectancy may be markedly diminished in more severely affected patients ²². In addition, long-term damage, such as loss of fingers or toes and facial cartilage or contractures of the hands, can have a significant impact on patients’ quality of life, psychiatric well-being, and functional status with regard to daily life and ability to work.

Successful bone marrow (BMT) or hematopoietic stem cell (HSCT) transplantation is the only curative approach, but is accompanied by specific risks of complications and should be considered in children with severe skin and bone marrow involvement ¹. The age of children with congenital erythropoietic porphyria (CEP) receiving bone marrow transplantation (BMT) ranges from younger than one year to 13 years ³⁶. Some of the first individuals with congenital erythropoietic porphyria (CEP) to successfully undergo bone marrow transplantation in childhood are now in their 20s ³⁹, ⁴⁶. Although there is limited information available regarding their long-term outcome post receiving bone marrow transplantation (BMT), experts have learned that individuals successfully transplanted have essentially no photosensitivity to artificial light sources or sunlight.

Several cases of late-onset congenital erythropoietic porphyria (CEP) have been reported in patients older than 50 years of age who presented with skin congenital erythropoietic porphyria (CEP) symptoms and increased porphyrin metabolite excretion, though at a lower level than in patients with the classic infantile-onset congenital erythropoietic porphyria (CEP) presentation ¹⁶. In several cases, the occurrence of congenital erythropoietic porphyria (CEP) symptoms was associated with the presence of myelodysplastic syndrome (a group of blood cancers where the bone marrow doesn’t produce enough healthy blood cells leading to a deficiency in red blood cells, white blood cells, and platelets, causing symptoms like fatigue, increased risk of infection, and easy bruising or bleeding) and neither germline nor somatic mutations in UROS or GATA1 were detected [39–41]. However, low-level mosaicism in the bone marrow may not be picked up by sequencing methods, but may be sufficient to cause an accumulation of porphyrin metabolites resulting in an attenuated phenotype ⁹⁰, ⁷⁰, ⁹¹.

Recently, one 60 year-old male patient was described with late-onset skin porphyria symptoms and a urinary porphyrin metabolite pattern consistent with congenital erythropoietic porphyria (CEP). He was heterozygous for the common UROS gene mutation encoding p.C73R, but a second mutation was not detected. He did not have myelodysplastic syndrome or another underlying hematologic abnormality. While the exact pathophysiology was unclear in the absence of a second disease-causing mutation, acquired mosaicism in the bone marrow affecting the UROS gene was hypothesized to be the underlying cause ⁹².

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