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Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Laboratory results
  6. Discussion
  7. What’s already known about this topic?
  8. Acknowledgments
  9. References

Background  Congenital erythropoietic porphyria (CEP) is an autosomal recessive cutaneous porphyria caused by decreased activity of uroporphyrinogen III synthase (UROS). Its predominant characteristics include bullous cutaneous photosensitivity to visible light from early infancy, progressive photomutilation and chronic haemolytic anaemia. Due to its rarity and genetic heterogeneity, clinical phenotypes are unclear and its impact on health-related quality of life (HRQoL) has not been previously assessed.

Objectives  To define comprehensively CEP phenotypes and assess their impact on HRQoL, and to correlate these factors with laboratory parameters.

Methods  A single observer assessed patients with CEP from four European countries.

Results  Twenty-seven unrelated patients with CEP, aged between 7·6 and 65 years, participated in the study. The patients came from the U.K. (17), France (4), Switzerland (4) and Germany (2). Additional data were obtained for two deceased patients. Newly characterized features of CEP include acute-onset cutaneous and noncutaneous symptoms immediately following sunlight exposure, and pink erythematous facial papules. There was a lack of consistent genotype–phenotype correlation in CEP. The main poor prognostic factors in CEP are the early age of disease onset and haematological complications.

Conclusions  CEP is a multisystem disease; cutaneous, ocular, oral and skeletal manifestations also contribute to disease severity and impact on HRQoL, in addition to the haematological complications. The rarity of the disease can lead to delayed diagnosis. The lack of consistent genotype–phenotype correlation in CEP suggests a contribution to phenotype from other factors, such as environment, patients’ photoprotective behaviour and genes other than UROS. There is currently an unmet need for multidisciplinary management of patients with CEP.

Congenital erythropoietic porphyria (CEP; OMIM 263700) is a rare autosomal, recessive, cutaneous porphyria. It is caused by deficiency of uroporphyrinogen III synthase (UROS), the fourth enzyme of the haem biosynthetic pathway.1–3 To date, 45 different CEP-causing mutations have been identified throughout the UROS gene on chromosome 10q25.2–26.3.4–6 CEP typically presents with passage of red urine shortly after birth. Lifelong bullous cutaneous photosensitivity to visible light and skin fragility start in early infancy, leading to scarring with photomutilation. Other manifestations include hypertrichosis, erythrodontia, chronic haemolytic anaemia, osteoporosis, corneal ulceration and scarring. Disease severity in CEP can range from fetal hydrops in utero to adult-onset mild cutaneous photosensitivity.7,8 To date, more than 200 cases of CEP have been described in the literature as single case reports or small case series.9,10 Due to its rarity and genetic and phenotypic heterogeneity there is currently a lack of a comprehensive, unbiased clinical description of CEP.

The aim of this research was to study a large cohort of patients with CEP in order to describe comprehensively the clinical and laboratory features of the disease and its impact on health-related quality of life (HRQoL). This knowledge would be invaluable for informing management decisions in CEP.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Laboratory results
  6. Discussion
  7. What’s already known about this topic?
  8. Acknowledgments
  9. References

Patients

The study was conducted on a U.K.-wide basis in collaboration with porphyria centres from three member countries of the European Porphyria Network (France, Germany and Switzerland). The study was approved by the U.K. multicentre research ethics committee (reference 06_MRE09_36F) and the local ethics committees of the three collaborating centres. Patients of all ages with a biochemically confirmed diagnosis of CEP were included in the study. Those with acquired CEP secondary to haematological diseases were excluded.

Individuals with CEP throughout the U.K. were identified via databases and personal communication with the porphyria units in Cardiff, London, Manchester, Leeds and Dundee. The hospital clinician or general practitioner (GP) of each patient was sent details of the study and asked for permission to invite their patient to participate in the study. Only patients under follow-up by the collaborating centres were included in France, Germany and Switzerland via invitation by the lead clinician of each centre.

All patients were seen by a single investigator (R.P.K.), as a single appointment, over a 12-month period following written informed consent/assent. U.K. patients were seen at their local hospital or GP surgery. Patients from France, Germany and Switzerland were seen either in their respective collaborating centre or at home. Prior to each meeting, the investigator carried out a detailed review of the patient’s medical records to obtain details of previous investigation results and treatments. The case notes of the two deceased patients with CEP from the U.K. were also reviewed.

Clinical and health-related quality of life assessment

A standardized pro forma was used to record the clinical history and examination findings for each patient. Photographs of consenting patients were taken by the investigator using a digital camera according to a predetermined photographic protocol.11

The HRQoL of patients was assessed using validated age-appropriate dermatology-specific questionnaires [Dermatology Life Quality Index (DLQI)12 for adults and the text version of the Children’s Dermatology Life Quality Index (CDLQI)13 for those below the age of 16 years] and a general health-related questionnaire (EuroQoL).14 The impact of CEP on the HRQoL of the patients’ close relative/spouse was assessed using the Family Dermatology Life Quality Index (FDLQI).15 DLQI, CDLQI and FDLQI scores each range from 0 (no impairment) to 30 (maximum impairment of HRQoL). The EuroQoL visual analogue scale (VAS) ranges from 0 (worst imaginable) to 1 (best imaginable health state).

Laboratory investigations

Blood and urine samples were obtained from each patient for the investigations listed in Tables 1 and 4, which included renal and liver function (LFT), direct Coomb’s test, UROS DNA and mRNA, and GATA1 DNA in five patients whose UROS mutations were not identified.16 All the samples (unless stated otherwise) were analysed in clinical pathology-accredited laboratories at the University Hospital of Wales, Cardiff, U.K. according to standard methods. Blood and urine samples for porphyrin analysis were photoprotected in transit. Because of the risk of being unsuitable for analysis due to the time lag from obtaining the samples in the non-U.K. centres to analysis in Cardiff, the following investigations were performed at the local collaborating laboratories: full blood count, reticulocyte count, direct Coomb’s test, renal function and LFT. In addition, UROS DNA was also analysed in the local collaborating laboratories.

Table 1.   Summary of the clinical data of the 29 patients with congenital erythropoietic porphyria
CaseSexAge at study (years) UROS genotypeAge at onsetSymptoms and signs at onsetDisease progression
  1. BMT, bone marrow transplantation; DCD, deceased; F, female; G6PD, glucose-6-phosphate dehydrogenase; HA, haemolytic anaemia; HS, hepatosplenomegaly; HT, hypertrichosis; J, jaundice; LFT, liver function tests; M, male; NF, not found; PPM, progressive photomutilation (there was a broad range in severity between patients); PS, photosensitivity; RU, red urine; TP, thrombocytopenia. aPreviously unpublished UROS mutation. b30 weeks’ gestation. cTransfusion-independent. dTransfusion-dependent.

1M56·8G225S/NF2·5 yearsRU, PS, skin fragility & blistersHAc, progressive pancytopenia & HS since aged mid-30s, PPM, ectropion aged 40s
2M31IVS9+4delA/IVS9+4delA13 yearsRU, PS, HT, skin fragility & blistersNone
3F12·3C73R/S212PBirthRU, pancytopeniad & HSPS, blisters, onycholysis by 6 months, BMT
4M29·4G225S/T228M6 yearsRU, PS, skin fragility & blisters, HSMild HA aged mid-20sc, PPM
5M20·8C73R/NFBirthRU, JPS, skin fragility, blisters, onycholysis by 6 months, anaemia at 3·5 yearsd, osteoporotic fractures since aged 4 years, nephrotic syndrome at 10·5 years, PPM, failed BMT
6M28·5IVS2+1G>A/ c.-86C>Ga3·5 yearsRU, PS, skin blisters, splenomegaly, HAcHAd & recurrent bilateral corneal ulcers since aged 9 years, osteoporosis in teens, PPM
7M7·6G188W/G188WBirthRU, J, pale (?anaemia)HAd & mild TP at 2 months, PS, skin erythema & desquamation (no blisters) by 3 months. Diagnosed G6PD deficiency (Mediterranean variant) by 3 months, BMT
8M41G225S/c.−90C>A4 monthsRU, PS, skin fragility & blistersHAd & splenectomy by 3·5 years, osteoporotic fracture by 3–4 years, conjunctival & corneal scarring at 14 years, PPM
9M56·6G225S/c.−76G>A5 yearsRU, PS, skin fragility & blistersPPM
10F22·8C73R/IVS8–23A>GBirthRU, JPS, skin blisters, mild HA aged 2 yearsc, PPM
11F20·2C73R/NFBirthRUPS, skin fragility & blisters 4 years, HT 7 years, PPM
12F12·2NF/NFBirthRUPS, acute burning & delayed blisters 1 year, HT 4 years, mild anaemia aged 5 yearsc. BMT
13F24·3NF/NFBirthRU, JPS & acute erythema 5 months, blisters due to skin fragility 5 years, HT 11 years
14M9·4IVS9+4delA/IVS9+4delA5 yearsRU, PS, skin blistersHT 6 years
15M14·2L237P/L237P3 daysRUHT 2 years, fragility 2·5 years, PS & blisters 10 years, cmild HA aged 2·5 years
16F11·5L237P/Del exon 2 & 3aBirthRUPS & skin blisters 1 year, HT 5 years, HAd & TP 4 years, massive HS by 8 years, BMT
17F14·8NF/NF2·5 yearsRU, PS, skin blisters.Mild HA aged 14·5 yearsc
18F11·6C73R/C73R30 weeksbFetal ascites, RU, J, HS, TP, abnormal LFTs at birthPS & skin blisters 3 months, anaemia 2 monthsc, BMT
19M32·7T228M/c.−70T>Aa1·5 yearsRU, PS, skin fragility & blistersMild HAc, scleral ulcer early 30s, PPM
20F52F195Ia, S197Ga/NF40 yearsPS, skin fragility & blistersNone, never had RU
21F39·8G58R/G58R4·5 yearsRU, PS with burning of perioral skin & blistersMild anaemia since childhoodc
22M19·4L237P/L237P2 yearsRU, PS, skin fragility & blistersPPM by 10 years, mild microcytic anaemiab & bilateral scleral thinning since early teens & blind in one eye
23M42·5C73R/C73RBirthRU, J, cyanosis & anaemia, PS & blisters aged 1 day post-phototherapy for neonatal JAnaemia only at birthd, PPM, chronic renal failure aged 32 years (haemodialysis since aged 41 years), corneal ulcers 42 years
24M58·4c.661–31T>G/ c.661–31T>GBirthRUPS, acute erythema & itching, delayed blisters by 10 years, PPM, HAd at least since aged mid-20s, corneal ulcers, blind in both eyes, osteoporosis 50 years
25F65L4F /c.−86C>A13 yearsSkin fragility, blisters & scarsRU aged 20 years
26M33·2T228M /T228M25 yearsPS with pain & swelling of lips, skin fragility & blistersNone, never had RU
27M29·2L4F /T228M10 yearsSkin fragilityPinkish urine, PS & skin blisters aged 16 years
28FDCDV82F /NF30 yearsRU, PS, HT, skin blistersPPM, scleral thinning & band keratopathy of cornea, osteoporosis. Died aged 74 years 9 months due to high-grade non-Hodgkin B-cell lymphoma
29MDCDL237P /Del exon 2 & 3aBirthRUPS, blisters & skin fragility aged 1 year, anaemia by age 6 years, abnormal bone texture on X-ray, hypersplenism with TPd & anaemiad. Died aged 10 years 10 months due to haemorrhagic complications
Table 2.   Summary of the different manifestations of congenital erythropoietic porphyria
Area of bodyManifestationsAdditional comments
SkinCutaneous photosensitivity to visible light, skin fragility, blistering, scarringCutaneous manifestations of all patients were confined to photoexposed sites. Photosensitivity in the visible light wavelength (400 nm) was confirmed in three patients by monochromator light tests
NailsLongitudinal ridging, subungual blisters, hyperkeratosis & haematomas, onycholysis/shedding, rudimentary nails, anonychiaSixteen individuals had a history of nail involvement, fingernails more affected than toenails. Onset as early as 6 months of age
HairFacial hypertrichosis and/or scarring, alopecia of the scalp due to recurrent blisteringTwenty-one male and female patients had facial hypertrichosis of varying severity; onset between the ages of 2 and 12 years. Three had scarring alopecia of the scalp with the onset age from 5 years to early 20s. Five had a combination of facial hypertrichosis and scarring alopecia of the scalp
HaematologyMild asymptomatic anaemia to severe transfusion-dependent haemolytic anaemia or pancytopeniaBlood films of 15 patients were reported to demonstrate nucleated red blood cells (RBCs), poikilocytosis, anisocytosis. Bone marrow examination in 10 patients reported fluorescent nucleated RBCs, erythroid hyperplasia and immature granulopoiesis. RBC survival studies with radioactive 51Cr and 59Fe in two patients demonstrated decreased RBC half-life, ineffective erythropoiesis and sequestration of RBCs with haemolysis in the spleen
SkeletonScarring of fingers resulting in fixed flexion deformities & resorption of finger tips, osteomyelitis, osteoporosisFourteen were affected to varying severity by loss of soft tissue, ranging from loss of fingertips to complete loss of distal phalanges affecting hand function. Four affected by osteoporosis (cases 5, 6, 8 and 24)
EyesPhotophobia to direct sunlight & bright visible light. Eyelids: blepharitis, meibomian cysts, loss of eyelashes, ectropion ± lagophthalmos Ocular: sclerokeratitis, lipid keratopathy, scleromalacia, conjunctivitis conjunctival and corneal ulcers and scarring Vision: hazy vision in two, two individuals registered blindFive gave a history of mild to moderate, life-restricting photophobia to direct sunlight and/or bright artificial light Inability to close the eyelids made the cornea and sclera vulnerable to mechanical trauma and phototoxic damage Cases 6 and 8 had evidence of corneal scarring and opacities and complained of hazy vision Case 22 was blind in the right eye and case 24 was registered blind in both eyes due to recurrent corneal ulcers; both were noted to have cloudy corneas Eleven patients regularly wore sunglasses, some with broad wraparound frames or leather shields, to maximize eye protection from direct sunlight
MouthErythrodontia, microstomia, gum recession, dental caries and overcrowding of teethTwenty-five had discoloration of deciduous teeth while 23 had lighter discoloration of permanent teeth ranging from light yellow to erythrodontia. Five developed microstomia between the ages of 10 and 50 years. Buccal mucosa was normal in 22 but could not be examined in five due to microstomia
LiverNeonatal jaundice, abnormal liver function tests (LFTs), hepatomegalySix had transient neonatal jaundice, some in isolation, some associated with anaemia. Eleven had abnormal LFTs with onset from birth to mid-30s; of these five had a history of transfusion-dependent severe haemolytic anaemia. Severity ranged from spontaneous resolution, asymptomatic and nonprogressive to cirrhosis in one. Nine had hepatomegaly ranging in onset from birth to aged mid-30s. Extent ranged from ultrasound scan finding to massive hepatosplenomegaly causing respiratory compromise
SpleenSplenomegaly and secondary pancytopeniaEleven had splenomegaly, ranging in onset from birth to adulthood. Extent ranged from ultrasound scan finding to massive hepatosplenomegaly resulting in respiratory compromise due to increased intra-abdominal pressure in one and death from complications of pancytopenia in one

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Laboratory results
  6. Discussion
  7. What’s already known about this topic?
  8. Acknowledgments
  9. References

Patient data

The study cohort consisted of 27 unrelated patients [from the U.K. (17), France (4), Switzerland (4) and Germany (2)].10 This comprised 15 male and 12 female patients with a mean age of 29·5 years (range 7·6–65 years) at the time of the study. Their ethnic origins were white (15), Asian (9), Middle Eastern (2) and North African (1). Data were also obtained for two additional deceased patients from the U.K., including one whose surviving sibling participated in the study. The clinical data of the 29 patients with CEP are summarized in Table 1.

Disease onset and diagnosis

The age of onset of the first signs and/or symptoms of CEP ranged from 30 weeks’ gestation (with fetal ascites) to 40 years of age (mean 5·7 years, median 1·75 years). Disease onset was before the age of 5 years in 76% (22/29) of cases. In 12 out of the 29 cases (41%) there was one or more manifestation of CEP present at birth that preceded the onset of cutaneous manifestations; these included red urine (12), jaundice (6), anaemia and/or thrombocytopenia requiring blood and/or platelet transfusions in the neonatal period (2) and hepatosplenomegaly (2). In 16 cases disease onset was between the neonatal period and 10 years of age and presented with red urine (13), cutaneous photosensitivity (14), skin blistering (15), skin fragility (8), hepatosplenomegaly (2), anaemia (1) and perioral oedema and pain (1). The six patients whose disease onset was after the age of 10 years presented with cutaneous manifestations with or without the history of red urine; this included three patients whose disease onset was after the age of 20 years. The duration between the onset of the first signs and/or symptoms and diagnosis of CEP ranged from 8 days to 48 years (mean 8·1 years, median 1·5 years). There was no clear correlation between this time interval and disease severity at presentation.

Disease manifestations

Manifestations of CEP in individual systems are summarized in Table 2.

Cutaneous features

All patients gave a history of photosensitivity of exposed skin to direct visible light, mainly sunlight, and artificial light in some cases. The time between direct exposure to light and the onset of symptoms and/or signs was broadly in two categories: 12 patients gave a history of acute-onset cutaneous symptoms (burning, itching, tingling, pinprick sensation) while seven also developed skin signs (erythema, blisters, mild swelling of the lips and skin) immediately following exposure to bright sunlight. Six described acute-onset noncutaneous symptoms immediately following exposure to direct sunlight, which lasted for up to 24 h postexposure; these were excess tears, photophobia, rhinorrhoea, headache, vasovagal symptoms, diarrhoea and vomiting. Six described delayed onset of cutaneous symptoms between 2 and 24 h following exposure to direct sunlight, which lasted from a few hours up to 3 days. These included itching and hypersensitivity or soreness at sites of subsequent skin blistering of exposed skin. All 29 patients had a history of recurrent, delayed-onset cutaneous signs on light-exposed sites, as summarized in Table 2.

Ten patients gave a history of worsening of cutaneous symptoms and/or signs during the course of the summer months each year. Fourteen did not experience any cutaneous symptoms and/or signs during winter months, while 13 experienced either similar or less severe symptoms than during the summer months. Over their lifetime, 17 patients perceived that their cutaneous manifestations had improved with less photosensitivity and blistering; the patients’ perception of the cause for this improvement included better photoprotection, hypertransfusion and emigration from tropical countries of birth to Europe. However, 12 patients felt that skin fragility, mainly of the hands, had worsened over time causing blistering and further scarring associated with resorption of fingertips to varying degrees. None of the 29 patients had a history of skin malignancy.

Haematological features

Haematological complications were the main predictor of poor prognosis for CEP. Those with CEP disease onset between birth and the age of 5 years were more likely to develop severe, progressive haematological manifestations. These included the following: neonatal jaundice, transfusion-dependent haemolytic anaemia and/or thrombocytopenia and splenomegaly. These patients required chronic hypertransfusion and/or splenectomy and/or bone marrow transplantation (BMT) in childhood;17 one child succumbed to the complications of pancytopenia aged nearly 11 years. Those with a history of disease onset after the age of 10 years, mainly with cutaneous manifestations, did not develop any clinically significant haematological manifestations. There was no history of haematological malignancies in the study cohort except for case 28, who died aged 74 years due to high-grade non-Hodgkin B-cell lymphoma unrelated to her CEP.

Skeletal features

Four patients with severe chronic transfusion-dependent haemolytic anaemia also developed osteoporosis, confirmed by radiology, between the ages of 4 and 57 years. Bone biopsy in two patients with osteoporosis (cases five and eight) demonstrated marked reduction in bone volume and widening of osteoid seams consistent with a defect in mineralization. Both these patients also had serum 25-hydroxyvitamin D [25(OH)D] levels in the deficient (< 10 ng mL−1) or insufficient (< 10–20 ng mL−1) ranges from early childhood to adulthood. The majority of patients did not have routine radiological skeletal surveillance. Of the nine who did, cases 1 and 16 were noted to have bone resorption of the distal phalanges on X-ray. Serial serum 25(OH)D and calcium levels were not available for most patients. However, three individuals with repeated low serum 25(OH)D levels had no skeletal manifestations of osteoporosis or vitamin D deficiency.

Offspring of patients with congenital erythropoietic porphyria

Three of the women with CEP had a total of five successful pregnancies with unrelated partners, resulting in healthy, unaffected children. Obstetric notes for cases 21 and 25 were not available for review. The details of case 10’s elective caesarean section under subdued operating theatre lighting, to minimize light exposure of the patient’s pelvic viscera and the neonate, has been published.18 Five of the men with CEP fathered a total of eight unaffected children with unrelated partners.

Miscellaneous features

The following clinical features were reported by more than one patient: recurrent episodes of prolonged epistaxis despite normal platelets and coagulation screen (3), pancreatitis with no identifiable cause (3) and renal disease (2). Case 5 developed nephrotic syndrome due to membranous glomerulonephritis aged 10·5 years, which was concluded to be idiopathic. However, he had been treated with chronic hypertransfusion from the age of 3·5 years, and iron pigment was noted on his renal biopsy. Case 23, who was transfusion-independent, developed chronic nephritic syndrome due to mesangioproliferative glomerular nephritis requiring haemodialysis from the age of 32 years.

The spectrum of clinical features observed

The cutaneous scarring in the present CEP cohort ranged from subtle to photomutilation on the face with loss of nasal and helical structures, ectropion and microstomia (Fig. 1a,b). The hands were the most severely affected sites in all patients, including those with mild phenotypes; the lower limbs were the least affected. The macroscopic appearance of the photoprotected patients’ urine ranged in colour from clear to red and showed pink fluorescence under Wood’s light. Clear urine was noted in the four long-term successful post-BMT patients (cases 3, 7, 12 and 18) and the two patients whose disease onset was after the age of 20 years (cases 20 and 26).

image

Figure 1.  (a) Examples of the spectrum of cutaneous disease severity of the face, hands and feet of patients with congenital erythropoietic porphyria (CEP) in the study cohort. (b) Examples of the spectrum of disease severity of the ocular, periocular, oral and perioral skin and ears of patients with CEP in the study cohort. Note the relative sparing of the feet even in those with severe photomutilation of the face and hands. Furthermore, note the markedly different clinical phenotype between cases 15 and 22 with identical genotypes (L237P/L237P).

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Newly reported clinical features of congenital erythropoietic porphyria

Five patients with different genotypes had multiple, asymptomatic, pink/erythematous soft papules on the nasolabial and perioral regions, previously unreported in CEP (Fig. 2). The histology of a papule biopsied from one patient suggested this to be a hamartoma.

image

Figure 2.  Multiple pink/erythematous papules on the nasolabial and perioral regions previously unreported in congenital erythropoietic porphyria.

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Impact of congenital erythropoietic porphyria on health-related quality of life

Table 3 summarizes the HRQoL data of the 27 patients with CEP. The mean DLQI score of the 19 adult patients was 8·2 (range 0–20, median 6). Seven out of the eight children completed the CDLQI; the mean score was 4 (range 0–10, median 5). Case 7 was not able to complete the CDLQI due to autism. Based on the DLQI banding,19 CEP had an overall very large impact on the HRQoL of six of the adults, a moderate impact on five, a small impact on six and no impact on two adult patients. Based on the CDLQI banding,20 CEP had an overall moderate impact on the HRQoL of one child, a small impact on three and no impact on three children. The highest-scoring domain and thus the highest impact of CEP on the DLQI was ‘leisure activities’, and on the CDLQI it was ‘school’ due to one or more of the following: photosensitivity, skin fragility, risk of osteoporotic fractures and/or need for frequent blood transfusions. The lowest-scoring domain and thus the lowest impact factor of CEP for both the DLQI and CDLQI was ‘relationships’.

Table 3.   Health-related quality of life data of the 27 patients with congenital erythropoietic porphyria
CaseSexAge (years)aDLQI or CDLQIFDLQIbEuroQoL 5DEuroQoL VAS
  1. aAge at the time of the study. bRelationship of the person completing the FDLQI to the patient. cCDLQI scores. DLQI, Dermatology Life Quality Index; CDLQI, Children’s Dermatology Life Quality Index; FDLQI, Family Dermatology Life Quality Index, DLQI, CDLQI and FDLQI scores range from 0 (no impairment) to 30 (maximum impairment of health-related quality of life); EuroQoL 5D, EuroQoL 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression each scored as ‘no problem’ = 1, ‘some/moderate problem’ = 2 or ‘unable to/an extreme problem’ = 3); EuroQoL VAS = EuroQoL visual analogue scale, scored from 0 (worst imaginable) to 1 (best imaginable health state). Case 7 was not able to complete the CDLQI questionnaire due to autism. His mother completed the EuroQoL proxy version.

1Male56·81812 (Wife)222210·64
2Male3100 (Wife)111110·90
3Female12·30c0 (Father)111110·99
4Male29·461 (Wife)112210·85
5Male20·81026 (Mother)223220·83
6Male28·5135 (Mother)222320·70
7Male7·66 (Mother)232230·50
8Male41131 (Parents)222220·47
9Male56·679 (Wife)111210·79
10Female22·81011 (Mother)222210·83
11Female20·220 (Mother)111210·90
12Female12·26c23 (Mother)112110·80
13Female24·30 111110·90
14Male9·45c8 (Mother)111110·65
15Male14·21c5 (Father)111110·70
16Female11·510c18 (Father)112110·90
17Female14·86c2 (Father)111220·90
18Female11·60c0 (Mother)111110·95
19Male32·717 112310·60
20Female524 111220·95
21Female39·86 222210·80
22Male19·4213 (Father)112111·00
23Male42·5188 (Mother)122310·80
24Male58·42018 (Wife)133210·40
25Female655 111111·00
26Male33·23 111110·70
27Female29·22 211111·00

The mean EuroQoL VAS score of the 19 adults was 0·79 (range 0·6–1·0, median 0·83) and of the eight children it was 0·77 (range 0·5–0·99, median 0·75). Of the EuroQoL 5D scores, in adults, 10 had moderate and three had extreme pain or discomfort due to CEP-related fissures and/or osteoporosis. Nine adults had some problem while two were unable to perform usual activities due to photomutilation of the hands and/or visual impairment (Fig. 3). Three children had some difficulty performing usual activities and two had moderate pain or discomfort due to their CEP. One child expressed moderate anxiety/depression due to the scarring on her hands. Seven adults and one child had some problems with mobility due to photosensitivity to sunlight while walking outdoors rather than due to physical immobility. However, one previously had some problems with mobility due to severe pain from osteoporosis.

image

Figure 3.  Examples of photomutilation affecting hand function such as making a fist or holding a pen.

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The mean FDLQI of a parent or spouse of 20 patients was 8·1 (range 0–26, median 7); the mean FDLQI of a parent or spouse of the 12 adult patients was 8·7 (range 0–26, median 8·5) and the mean for parents of the eight children was 7·8 (range 0–23, median 5·5).

Two children who had received successful BMTs and their parents each scored 0 on the CDLQI and FDLQI implying no impairment on HRQoL. Case 24 and his wife had high DLQI and FDLQI scores consistent with his severe disease phenotype. However, there were no consistent correlations between the HRQoL scores of the cohort or their relatives with disease severity or laboratory investigation results. For example, case 22, with severe photomutilation and blindness in one eye, had a low DLQI score of 2 whereas his father had a FDLQI score of 13.

Management of congenital erythropoietic porphyria

The management and outcomes of this study cohort are detailed in a second paper.17

Laboratory results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Laboratory results
  6. Discussion
  7. What’s already known about this topic?
  8. Acknowledgments
  9. References

The laboratory test results of this cohort are summarized in Table 4. Based on serum 25(OH)D levels, 22% (6/27) were deficient (< 10 ng mL−1) and 48% (13/27) were insufficient (10–20 ng mL−1) in vitamin D. Three patients with insufficient and one with normal vitamin D levels were on some form of oral vitamin D supplements at the time of the study (e.g. 400 IU colecalciferol, alfacalcidol). Two had secondary hyperparathyroidism. There was no clear correlation between serum vitamin D levels and either clinical severity, extent of photoprotection or porphyrin levels.

Table 4.   Laboratory test results of the 27 patients with congenital erythropoietic porphyria during the present study
Investigation (normal range)Non-BMT/ non-hypertransfusion. Mean (range), n = 18Chronic hypertransfusion. Mean (range), n = 4Post-BMTa
(Cases 3, 7, 12, 18)Mean (Case 16)Range
  1. AST, aspartate transaminase; BMT, bone marrow transplant; Ca, corrected serum calcium; LDH, lactate dehydrogenase; PTH, parathyroid hormone; TUP, total urine porphyrin. aMean post-BMT patient results are presented in two columns, as case 16 was only 3 months post-BMT at the time of the study. bSerum 25-hydroxyvitamin D (ng mL−1): < 10, deficient; 10–20, insufficient; ≥ 30, optimum.

Total plasma porphyrin (< 11·2 nmol L−1)1721 (42·6–9536)3313 (1133–5007)49·5466·9(6·8–467)
Total erythrocyte porphyrin (0·4–1·7 μmol L−1)13 (3·3–23·8)23·8 (4·3–44·4)0·93(0·6–3)
TUP : creatinine ratio (< 34 nmol mmol−1)4991 (209–15 337)11 494 (1920–27 854)236·52546(17–2546)
Haemoglobin (11·5–15·5 g dL−1 adult female; 13–16·6 g dL−1 male)13 (9·9–16·5)10 (6·5–13)13·411·1(11·1–14·5)
Reticulocytes (0·2–2%)3·1 (0·6–7·9)1·4 (0·4–2·1)11(0·4–2·1)
White blood cell count (3·5–11 × 109 cells L−1)5·9 (2·2–17·3)6·9 (2·4–16·4)6·711·1(5·9–11·1)
Platelet count (150–400 × 109 cells L−1)197 (79–383)157 (68–311)218265(179–265)
Haptoglobin (0·7–3·79 g L−1)1·8 (0·8–3·1)< 0·382·5< 0·38(0·99–4·0)
Creatinine (70–120 μmol L−1)107 (60–492)97 (53–200)6354(54–65)
AST (5–45 IU L−1)35 (14–71)48·5 (24–86)23139(22–139)
Bilirubin (1–22 μmol L−1)14·2 (7–26)21·5 (6–27)9·711(6–13)
Direct bilirubin (1–5 μmol L−1)6·5 (1·4–28)6·8 (1·5–10)18·56(4–33)
Ca (2·2–2·6 mmol L−1)2·34 (2·2–2·5)2·3 (2·1–2·4)2·32·4(2·3–2·4)
Serum 25(OH)Db22·2 (7·3–70·2)12·9 (8·2–22·9)18·219·8(11·5–31)
PTH (0·9–5·4 pmol L−1)5·7 (1·5–24·6)5·2 (2–6·7)54·8(4·6–5·6)
LDH (230–460 IU L−1)608 (262–1086)1226 (257–1787)400580(351–580)
Ferritin (15–300 mg L−1)153 (5–780)5183 (1772–8500)582227(27–2227)

Genotype–phenotype correlation

Table 1 summarizes the UROS genotypes of the 29 patients. Long-range polymerase chain reaction did not identify the site of breakpoints causing deletions of exons 2 and 3 in the second allele in cases 16 and 29. The UROS RNA was analysed in two patients in whom mutations were not identified in one of their UROS alleles. In one patient, the second allele was absent on RNA analysis. In the other patient, RNA analysis demonstrated both UROS alleles to be present, but the second mutation was not identified. In five patients (cases 1, 5, 6, 9 and 11) with unidentified UROS mutations the GATA1 gene was analysed but was not contributory.

Of the 10 patients with homozygous UROS mutations, five gave a history of parental consanguinity. Four identical UROS genotypes were shared by eight patients. Only U.K.-16 and U.K.-DCD-02, who shared the L237P/deletion of exons 2 and 3 genotype, were siblings, while the others were unrelated but shared the same ethnicity. The order of frequency of the common UROS mutations in the 58 alleles of the 29 patients in this study cohort are as follows: C73R, 13·8%; L237P, 10·3%; T228M, 8·6%; G225S, 6·9%; IVS9 + 4delA, 6·9% and L4F, 3·4%. C73R and G225S mutations were confined to white patients while L237P and IVS9 + 4delA were confined to Asian patients. Five different mutations were identified in the erythroid promoter region of the UROS gene in the compound heterozygous state in five unrelated patients.

The age and clinical severity at disease onset and disease progression correlated with the genotype in some cases, but not consistently. For example, the clinical phenotype was markedly different in two unrelated individuals (cases 15 and 22) with identical genotypes (Table 1, Fig. 1a,b).

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Laboratory results
  6. Discussion
  7. What’s already known about this topic?
  8. Acknowledgments
  9. References

This study is the first to define the broad spectrum of disease severity in a large cohort of patients with CEP.

Twenty individuals with a confirmed diagnosis of CEP living in the U.K. were identified during this study. Thus, the estimated crude minimum prevalence of CEP in the U.K. is one per three million population (U.K. population in mid-2007 at the time of this study was 60 975 000).21 The prevalence of CEP quoted as less than one per million population in the current literature has not been verified by references.1 The prevalence of CEP in the collaborating countries cannot be accurately estimated from the present study as only patients under follow-up by these centres were recruited.

There was a broad range in the age, manifestations and severity at disease onset in this cohort, as has been previously reported.9 Haematological manifestations were the most important predictors of disease prognosis in this cohort. Contrary to previous reports, not all patients in the present study gave a history of red urine at disease onset. Two patients with onset after the age of 20 years denied ever passing red urine. Acute-onset noncutaneous symptoms immediately following sunlight exposure have only previously been documented in two patients with CEP: one with occasional abdominal pain after sun exposure, in which the timing between exposure and symptoms was not documented;22 the other with episodes of fever and abdominal pain 1–2 days post-sun exposure.23

The onset, severity and progression of cutaneous photomutilation and ocular complications did not consistently correlate with the severity of the haematological complications; case 22 is such an example. The disparity in photomutilation of the hands and feet within an individual is likely to be due to susceptibility to a combination of insults from photodamage and skin fragility of the hands compared with the feet, which are protected by footwear.

The development of osteoporosis in this study correlated with the severity of anaemia in particular. Bone marrow hyperplasia due to chronic haemolytic anaemia in CEP is thought to cause osteopenia, widening of the medullary cavity, thinning of cortical and trabecular bones and increased bone turnover.24,25 The impact of serum vitamin D levels on skeletal manifestations in this study cohort is unclear, as the majority of patients had vitamin D insufficiency or deficiency. This was further confounded by the fact that the majority of patients did not have routine radiological skeletal surveys in order to correlate the impact of vitamin D insufficiency or deficiency on the skeletal manifestations of CEP. In a U.K.-wide study of 201 patients with erythropoietic protoporphyria (EPP), 17% had vitamin D deficiency and 63% had vitamin D insufficiency, both of which were significantly associated with total erythrocyte porphyrin (TEP) levels and inversely associated with duration of onset of symptoms following sunlight exposure.26 In this CEP cohort, there was no similar clear correlation. The cause of low serum vitamin D levels in CEP is probably due to sun avoidance in most cases. However, in the present cohort, three long-term post-BMT children, symptomatically cured of CEP and enjoying unlimited sunlight exposure and unrestricted diet, also had vitamin D insufficiency.

Management implications of neonatal jaundice in CEP with blistering following phototherapy are highlighted by case 23 and previous case reports.27–29 Thus, in suspected cases of CEP, asymptomatic neonatal jaundice may be managed conservatively. Similar precautions are required for the management of neonatal jaundice in unaffected neonates of women with CEP, as these neonates may be transiently photosensitive due to placental transfer of maternal porphyrinogens in utero (as in case 10).18 Nephrotic syndrome has previously been reported in three cases of CEP.30–32 Histological evidence of renal iron deposition was noted in one previous case with a history of repeated hypertransfusion similar to case 5.32 Pancreatitis in association with CEP has not been previously reported and may be coincidental. However, haemolysis may result in gallstone formation, which in turn can cause pancreatitis. Two patients with a history of pancreatitis had evidence of transfusion-independent haemolytic anaemia but no evidence of gallstones.

TEP level was the only laboratory parameter that was consistently normal in all patients symptomatically cured of CEP in the long term following BMT. The total plasma porphyrin and total urine porphyrin to creatinine ratios were normal (case 12) or much lower in successful post-BMT patients (cases 3, 7 and 18) and two patients with late-onset mild phenotypes (cases 20 and 26) compared with the rest of the study cohort.

This is the first study to formally assess the impact of CEP on the HRQoL of patients and their families. The mean CDLQI of the seven children with CEP (4) was much lower than that of 44 children with EPP (mean 12·8, median 13, range 5–21) from a large U.K.-wide study.33 The median DLQI of 6 (range 0–20, mean 8·2) in the 19 adults with CEP was higher than previously published median DLQI scores of U.K. patients with variegate porphyria (3, n = 45) and porphyria cutanea tarda (1·5, n = 57).34 However, the mean DLQI score of the current adult patients with CEP was lower than that of a U.K.-wide study of 176 patients with EPP (mean 14, median 14, range 0–29).33 The differences in CDLQI and DLQI scores between the patients with CEP and EPP may reflect the differences in the number of participants between the two studies, the broad phenotypic spectrum and chronic progressive nature of CEP and the more acute cutaneous symptoms associated with EPP.

Currently there are no published EuroQoL or FDLQI data relating to CEP or other cutaneous porphyrias. There was some concordance in patients’ scores between similar questions in the dermatology-specific and general health questionnaires. For example, cases 6, 19 and 23 scored ‘extreme discomfort’ on the EuroQoL and ‘very much’ or ‘a lot’ for the DLQI question relating to ‘sore, painful, stinging’.

The lack of consistent correlation between HRQoL scores and disease severity in CEP possibly reflects the relatively short time scale that is addressed by current HRQoL questionnaires, and adaptation of patients to a lifelong disabling disease. This also highlights the need for patient-reported assessment of disease severity in addition to that of the physician. Currently available, validated HRQoL questionnaires address most, but not all, issues that matter to patients. For example, these include difficulties related to activities of daily living such as difficulty with attending to personal hygiene, dressing and feeding, due to severe photomutilation causing decreased hand function and microstomia. These issues are only broadly but not specifically addressed by the EuroQoL. Similarly, the question relating to mobility in the EuroQoL does not specifically address the issue raised by eight patients with CEP in the current cohort, who reported problems with mobility outdoors in sunlight due to photosensitivity rather than physical immobility; these patients did not qualify for disability parking privileges. Furthermore, patients with severe photosensitivity reported being unable to use public transport due to lack of adequate photoprotected areas within these modes of transport. The impact of certain manifestations or treatment-related issues of this multisystem disease on HRQoL was not captured by either of the questionnaires used in this study. For example, patient-reported impacts of ocular manifestations on their HRQoL included patients and their close family members having to avoid woollen clothing due to irritation of the exposed cornea due to the loss of eyelashes and ectropion. Patients also reported difficulty with personal hygiene and premature discontinuation of careers due to visual impairment. The study cohort also expressed the impact of nondermatological treatments on their HRQoL, such as having to plan short holidays, for those requiring frequent hypertransfusions, and inability to swim due to indwelling intravenous catheters. Thus, in summary, the HRQoL issues need to be highlighted in a more objective and disease-specific manner in order to allocate resources for individuals with this disability disease. The development and validation of a Patient Generated Index such as that proposed for atopic dermatitis would address specific CEP-related HRQoL issues that matter to affected individuals.35

In theory, an individual’s UROS genotype would predict their residual UROS enzyme activity. This in turn would aid management decisions in individual patients based on their disease prognosis. In the present study, UROS genotypes correlated with phenotype in some patients as previously reported; for example, C73R homozygous mutation was associated with a severe phenotype while IVS9 + 4delA was associated with a milder phenotype.2,6 As previously reported, the phenotype in some individuals with identical genotypes was markedly different,6,22,36–38 but for the first time this disparity was clearly illustrated in the present study by cases 15 and 22 (Fig. 1a,b). Environmental and behavioural factors such as the extent of sunlight exposure and photoprotection measures may partly explain this discrepancy, and highlight the importance of addressing these issues in the management of CEP.

The genotypes of two-thirds of this cohort were unique to each individual. In addition, genotype–phenotype correlation was limited in some patients whose UROS mutations were not identified. The role of modifier genes, such as the ALAS2 gain-of-function mutation towards CEP phenotype, has recently been described.39 It is also possible that mutations in transcription factors other than GATA1, such as the TFCP2 gene, may influence UROS gene expression in patients with CEP whose UROS mutation has not been identified.40 Two different mutations were identified at the same nucleotide position (−86) in two unrelated patients with very different phenotypes (cases 6 and 25). Two different mutations (G188W and G188R) in the same nucleotide position (c.562 in exon 9) of the UROS gene resulting in two very different CEP phenotypes has previously been reported once.41,42 Case 20 was unique in having two mutations a few nucleotides apart on the same UROS allele, a phenomenon not previously reported in CEP. This individual also gave a history for the oldest age of disease onset (aged 40 years) in this study.

In conclusion, this study has comprehensively described the full clinical spectrum of CEP. Although some cases are mild, many are not; severe photomutilation is an inevitable outcome of many cases treated conservatively. There is a lack of consistent genotype–phenotype correlation suggesting that other nongenetic factors predict outcome; thus management decisions based on the concept of genotype–phenotype correlation alone cannot be justified. The main prognostic indicators were haematological manifestations; onset of haemolytic anaemia and/or thrombocytopenia by the age of 5 years predicted a poorer prognosis. Photoprotective behaviour influenced the severity of cutaneous and ocular photomutilation, independent of the haematological complications. This study confirms CEP to be a rare multisystem and extremely disabling disease that requires lifelong multidisciplinary clinical input. Routine clinical practice should include patient-administered HRQoL scores in the overall clinical assessment of this condition.

What’s already known about this topic?

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Laboratory results
  6. Discussion
  7. What’s already known about this topic?
  8. Acknowledgments
  9. References
  •  Congenital erythropoietic porphyria (CEP) is a rare heterogeneous bullous cutaneous porphyria.
  •  Due to its rarity, clinical descriptions of CEP are limited to single or small cohort case reports by different observers.

What does this study add?

  •  This study is the largest comprehensive single-observer clinical description of CEP to date.
  •  Previously unreported cutaneous and noncutaneous features of CEP are described.
  •  The genotype of CEP does not always consistently correlate with the clinical phenotype.
  •  This study includes the first formal assessment of the impact of CEP on health-related quality of life.

Acknowledgments

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Laboratory results
  6. Discussion
  7. What’s already known about this topic?
  8. Acknowledgments
  9. References

Patients and their families, Professor George Elder, Miss Amy Lake, Mr Richard Ellis, Mr Barry Francis, Professor Robert Newcombe, Dr Graham Shortland, Dr Jonathan Kell and Dr Joanne Marsden (U.K.), Dr Juergen Harms (Switzerland), Miss Viola Kürten (Germany), U.K. collaborating clinicians (Drs R. Dawe, C. Hambling, H. Hempel, L. Ingram, H. Jones, S. Kinsey, J. Lawrie, C. Lovell, S. Mendelsohn, C. Moss, A. Nasralla, V. Ratnayake, J. Ravenscroft, D. Rees, K. Ryatt, A. Sahota, C. Steward, S. White) and the European Porphyria Network.

References

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Laboratory results
  6. Discussion
  7. What’s already known about this topic?
  8. Acknowledgments
  9. References