<figure><img src="image_1.png" /></figure>

# Very Early Diagnosis and Management of Congenital Erythropoietic Porphyria

Marie-Pier Desjardins, MD-MSc<fnref n="1" />, Lamia Naccache, MD<fnref n="1" />, Audrey Hébert, MD-MHSc<fnref n="1" />, Isabelle Auger, MD<fnref n="2" />, Pierre Teira, MD-MSc<fnref n="3" />, and Marie-Claude Pelland-Marcotte, MD-PhD<fnref n="1" />

Clinical Pediatrics
2023, Vol. 62(5) 399–403
© The Author(s) 2022

<figure><img src="image_2.png" /></figure>

Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/00099228221128661
journals.sagepub.com/home/cpj

<figure><img src="image_3.png" /></figure>

SAGE

## Abstract

Congenital erythropoietic porphyria (CEP), a rare form of porphyria, is caused by a defect in the heme biosynthesis pathway of the enzyme uroporphyrinogen III synthase (UROS). Uroporphyrinogen III synthase deficiency leads to an accumulation of nonphysiological porphyrins in bone marrow, red blood cells, skin, bones, teeth, and spleen. Consequently, the exposure to sunlight causes severe photosensitivity, long-term intravascular hemolysis, and eventually, irreversible mutilating deformities. Several supportive therapies such as strict sun avoidance, physical sunblocks, red blood cells transfusions, hydroxyurea, and splenectomy are commonly used in the management of CEP. Currently, the only available curative treatment of CEP is hematopoietic stem cell transplantation (HSCT). In this article, we present a young girl in which precocious genetic testing enabled early diagnosis and allowed curative treatment with HSCT for CEP at the age of 3 months of age, that is, the youngest reported case thus far.

## Keywords

congenital erythropoietic porphyria, hematopoietic stem cell transplantation, hematology

## Introduction

Congenital erythropoietic porphyria (CEP) is a rare form of porphyria. This autosomal recessive inherited heme metabolism disorder is caused by a defect of the enzyme uroporphyrinogen III synthase (UROS), an enzyme in the heme biosynthesis pathway. Uroporphyrinogen III synthase deficiency leads to an accumulation of porphyrins in the erythroid precursors of bone marrow, red blood cells, and tissues such as skin, bones, teeth, and spleen.<fnref n="1" />⁻<fnref n="3" /> The exposure of nonphysiological accumulated porphyrins to sunlight causes oxidative stress leading to cell death.

More than 50 pathogenic mutations in UROS have been identified explaining the various clinical presentations of CEP ranging from severe antenatal manifestations causing hydrops fetalis to adult-onset mild cutaneous lesions.<fnref n="2" /> Congenital erythropoietic porphyria is characterized by severe skin photosensitivity and skin fragility, causing blisters, erosions, secondary skin infections, and later changes such as atrophy and mutilating scars. Accumulated porphyrins in the erythroid precursor of bone marrow and red blood cells result in ineffective erythropoiesis and long-term intravascular hemolysis. Other manifestations of CEP such as brown-red urine, erythroderntia, corneal ulceration,

osteoporosis, and pathological bone fractures are corollaries of excessive porphyrins deposition in tissues. The diagnostic of CEP is based on the markedly elevated levels of porphyrins in urine, clinically observed with a dark-brown staining of the diapers. High levels of porphyrins in red blood cells and feces are also noted. Genetic testing identifying UROS mutation confirms the diagnosis.

Patients suffering from CEP have a poor outcome and quality of life.⁴ Several supportive therapies such as strict sun avoidance, physical sunblocks, red blood cells transfusions,⁵ hydroxyurea⁶ and splenectomy⁷ are commonly used in the management of CEP.⁸ Currently,

## Corresponding Author:

Marie-Pier Desjardins, CHU de Québec, Centre Hospitalier de l'Université Laval, Department of Pediatrics, Université Laval, 2705 Boulevard Laurier, Quebec City, QC G1V 4G2, Canada.

Email: marie-pier.desjardins.5@ulaval.ca

<footnote n="1">¹CHU de Québec, Centre Hospitalier de l'Université Laval, Department of Pediatrics, Université Laval, Québec City, QC, Canada</footnote>

<footnote n="2">²CHU de Québec, Centre Hospitalier de l'Université Laval, Division of Dermatology, Department of Medicine, Université Laval, Québec City, QC, Canada</footnote>

<footnote n="3">³CHU Sainte-Justine, Division of Hematology/Oncology, Department of Pediatrics, University of Montréal, Montréal, QC, Canada</footnote>
<figure><img src="image_4.png" /><figcaption>**Figure 1.** (A) Blue-red skin papules eruption, (B) cutaneous blister on the pulse oximetry site and (C) erythrodontia (pictures provided with the family's authorization).</figcaption></figure>

the only available curative treatment of CEP is hemato-poietic stem cell transplantation (HSCT). In this article, we present, to our knowledge, the youngest case of suc-cessful HSCT for CEP.

## Case Description

A baby girl was born through vaginal delivery at 38 5/7 weeks of gestation, with severe symmetric intrauterine growth retardation (birth weight 2240 g, <3e percentile). Parents had a consanguineous union (third-degree cous-ins). This was the fourth pregnancy of a multiparous female, who had first lost twins during pregnancy (twin A: death in utero at 8-9 weeks of gestation; twin B: died at birth with anhydramnios, splenomegaly, extramedul-lary hematopoiesis, erythroblastosis, and cholestasis with hemosiderosis) and later had a healthy girl. This pregnancy was complicated by intrauterine growth retar-dation and other ultrasound abnormalities such as cystic hygroma at 12 weeks and later development of short femur, cardiomegaly, and pericardial effusion suggesting hydrops fetalis. Antenatal investigation including amnio-centesis, karyotype, comparative genomic hybridization (CGH), and infectious panel were noncontributory.

At birth, our patient presented with hepatospleno-megaly, hematuria, and blue-red skin papules eruption compatible with blueberry muffin rash (Figure 1A). She later developed a cutaneous blister on the pulse oxime-try site (Figure 1B).

Laboratories showed regenerative normocytic ane-mia (hemoglobin: 95 g/dL, reticulocytes count: 10.7%), thrombocytopenia (platelet count: 84 × 10⁹/L) and cho-lestasis (total and direct bilirubin: 100 µmol/L and 65 µmol/L [8× the upper limit of normal], respectively) without associated transaminitis. The complementary work up, including blood smear, Coombs test, activity of pyruvate kinase and hexokinase, lactate dehydroge-nase and infectious screening was negative.

The family history prompted an early genetic referral and genetic testing. An extended metabolism gene panel (Fulgent Genetics) revealed a homozygous mutation in the UROS gene, variant (c.217>C, p.[Cys73Arg,]) leading to the early diagnosis of CEP. The homozygous c.217T>C [p. Cys73Arg] mutation, resulting in a less than 1% of normal UROS activity, is correlated with severe phenotype leading to blood transfusion depen-dency from birth.⁹ Urinalysis showed markedly elevated levels of uroporphyrin and coproporphyrin (Figure 2).

Supportive management included strict sun avoidance, physical sunblocks, and blood transfusions. However, regarding the extremely young onset of the disease and the poor expected outcome, an allogenic HSCT was offered. Therefore, at 3 months of age, the patient received an unrelated HSCT from a 10/10 HLA identical donor. The conditioning regimen was based on busulfan (days -6 to -33; 5 mg/kg/dose), fludarabine (days -8 to -3; 1 mg/kg/dose) and alemtuzumab (days -8 to -6; 0.167 mg/ kg/dose). Cyclosporine and mycophenolate mofetil were
<figure><img src="image_5.png" /><figcaption>**Figure 2.** Levels of urinary porphyrins before and after HSCT in CEP.
Abbreviations: HSCT, hematopoietic stem cell transplantation; CEP, congenital erythropoietic porphyria.</figcaption></figure>

administered as graft-versus-host disease (GVHD) prophylaxis. Anti-infectious prophylaxis included antibacterial prophylaxis with amoxicillin, antifungal prophylaxis with fluconazole, and micafungin, trimethoprim, palivizumab, and weekly intravenously administered immune globulins. The neutrophil engraftment was achieved on day +15. Full donor chimerism was confirmed 2 months after HSCT.

The HSCT was complicated by thrombotic microangiopathy (TMA) and recurrent pericardial effusion. The patient developed TMA approximately around day +7, manifesting with acute kidney failure, pericardial effusion, hypertension, hematuria, and proteinuria combined with markedly elevated C5b9 in blood. Thrombotic microangiopathy was successfully treated with changing cyclosporine to prednisone and eculizumab. Recurrent pericardial effusion occurred during prednisone tapering with no sign of TMA. Treatment consisted of glucocorticoids (pulse of intravenous methylprednisolone followed by prednisone tapering), colchicine, fluid drainage, and ultimately pericardiectomy. She did not develop any signs of veno-occlusive disease or acute GVHD despite the discontinuation of cyclosporine 11 months after HSCT.

Two years after HSCT, the patient had a favorable outcome with significant reduction in urine porphyrins levels (although still remaining above the normal range) (Figure 2). Physical examination showed erythrodermia (Figure 1C) without any skin lesions or hepatosplenomegaly. A complete blood count showed a normalization of red cell and platelet counts. Echocardiography, electrolytes, renal function, albumin, and hepatic function were normal.

## Discussion

Several case reports have already proved the effectiveness of HSCT in the treatment of severe CEP.<sup>10-18</sup> However, our case report presents the impact of a very early diagnosis and management on the outcome of CEP. Our patient suffered from a severe form of CEP due to a homozygous mutation in the UROS gene p. Cys73Arg, the most frequent mutation of CEP. This mutation is also observed in the most severe form of CEP resulting in life-threatening neonatal manifestations or even *in utero* death.<sup>19</sup> Therefore, our patient underwent an unrelated HSCT from an HLA-matched donor at age 3 months.
Hematopoietic stem cell transplantation significantly improved levels of urinary porphyrins although they still remain above the normal range. It suggests HSCT might be used early on in patients with a very severe phenotype of CEP, before the occurrence of any irreversible complications.

In 1991, Kauffman et al²⁰ first described encouraging results after a bone marrow graft from a human leucocyte antigen (HLA) identical sibling in a 10-year-old girl with CEP, who eventually died of infectious complications. Early clinical recovery of skin lesions and an important diminution of urinary porphyrin excretion, although slightly above the normal range, were observed 9 months after transplantation, revealing for the first time the possible benefit of HSCT in CEP. Since, more than 25 successful cases have been described.¹⁰⁻¹⁸ A recent study presented 13 cases of HSCT in CEP, where 11 were still in remission 7 years after transplantation, and 2 died of infectious complications following HSCT.¹⁹ Besnard et al²¹ recently described the long-term complications post-HSCT of 6 patients during a maximum follow-up period of 25 years. Indeed, 4 patients had a favorable outcome with near-normal levels of porphyrins and no clinical manifestations of CEP while 1 died from severe GVHD and 1 from acute hepatic failure 1 year after HSCT.

Although allogeneic HSCT is known to be a curative treatment of CEP, the decision must be balanced with the risks of complications related to bone marrow transplantation.²² Accordingly, HSCT is currently reserved for individuals with severe forms of CEP. Currently, there is a lack of definitive criteria to identify the subgroup of patients suffering from a severe form of CEP, and hence a poor prognosis, who could benefit from HSCT. Moreover, the genotype-phenotype association lacks consistency, as patients with identical genotype may have various clinical presentations.⁴,²³ A recent publication proposed that patients with onset of hemolytic anemia or thrombocytopenia by the age of 5 years old have a poorer prognosis,⁴ suggesting that HSCT is indicated.

Early diagnosis is critical, permitting initiation of supportive care before the apparition of irreversible changes. Unfortunately, CEP can be difficult to diagnose with a reported median age of diagnosis of 7 months with typical red urine, CEP skin lesions and hemolytic anemia appearing at median age of 1, 2, and 8 months, respectively.²¹ Martinez Perinado et al¹² reported an early onset case of CEP who presented with severe post-delivery manifestations and underwent a matched unrelated HSCT at age 7 months. As CEP is a rare condition, a multidisciplinary evaluation led by the responsible pediatrician is necessary for early diagnosis and genetic testing. For our patient, genetic testing before 72 h hours

of life allowed the initiation of supportive care and ultimately HSCT.

Urinary porphyrin levels of our patient significantly improved but remain above the normal range. Several case reports of successful HSCT in the treatment of CEP also described a similar situation, notably a recent study describing near-normal biological levels of porphyrins 25 years after HSCT.²¹ The remaining elevated porphyrin levels, despite HSCT, might reflect the porphyrin production by nonerythroid tissues. Indeed, UROS deficiency is still present in nonerythroid tissues (i.e., liver cells) leading to a persistent accumulation of porphyrins despite full replacement of erythroid tissues with HSCT.² The safe threshold of urinary porphyrins for withdrawal of preventive measures remains unknown.

Hematopoietic stem cell transplantation is an effective treatment of CEP conditional to the availability of matched donors. New experimental gene therapies are being studied to overcome this limitation. de Verneuil et al²⁴ recently published about genetically modified hematopoietic stem cells, with a lentivirus-mediated vector, allowing the normal expression of the UROS gene to proceed to a bone marrow transplantation in a murine model of CEP. Results showed a complete enzymatic and phenotypic resolution of the disease, suggesting a promising scope for genetically modified HSCT.

To our knowledge, this case report describes the short-term benefits of HSCT in the youngest patient suffering from a severe neonatal phenotype of CEP. It suggests that early diagnosis and treatment might prevent the occurrence of devastating and irreversible consequences of CEP.

## Author Contributions

All authors contributed to the writing of the manuscript and approved the revised version.

## Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

## Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

## ORCID iD

Marie-Pier Desjardins ID

<figure><img src="image_6.png" /></figure>

https://orcid.org/0000-0001-9584-2320

## Consent

Written informed consent for patient information and images to be published was provided by a legally authorized representative.
## References

1. Wenner C, Neumann NJ, Frank J. [Congenital erythropoietic porphyria: an update]. *Hautarzt*. 2016;67(3):216-220.

2. Erwin AL, Desnick RJ. Congenital erythropoietic porphyria: recent advances. *Mol Genet Metab*. 2019;128(3):288-297.

3. Erwin A, Balwani M, Desnick RJ. Congenital erythropoietic porphyria. In: Adam MP, Ardinger HH, Pagon RA, et al. eds. *GeneReviews®*. Seattle, WA: University of Washington; 1993-2022.

4. Katugampola RP, Badminton MN, Finlay AY, et al. Congenital erythropoietic porphyria: a single-observer clinical study of 29 cases. *Br J Dermatol*. 2012;167(4):901-913.

5. Piomelli S, Poh-Fitzpatrick MB, Seaman C, Skolnick LM, Berdon WE. Complete suppression of the symptoms of congenital erythropoietic porphyria by long-term treatment with high-level transfusions. *N Engl J Med*. 1986;314(16):1029-1031.

6. Guarini L, Piomelli S, Poh-Fitzpatrick MB. Hydroxyurea in congenital erythropoietic porphyria. *N Engl J Med*. 1994;330(15):1091-1092.

7. Murphy A, Gibson G, Elder GH, Otridge BA, Murphy GM. Adult-onset congenital erythropoietic porphyria (Gunther's disease) presenting with thrombocytopenia. *J R Soc Med*. 1995;88(6):357P-358P.

8. Harada FA, Shwayder TA, Desnick RJ, Lim HW. Treatment of severe congenital erythropoietic porphyria by bone marrow transplantation. *J Am Acad Dermatol*. 2001;45(2):279-282.

9. Desnick RJ, Astrin KH. Congenital erythropoietic porphyria: advances in pathogenesis and treatment. *Br J Haematol*. 2002;117(4):779-795.

10. Dupuis-Girod S, Akkari V, Ged C, et al. Successful match-unrelated donor bone marrow transplantation for congenital erythropoietic porphyria (Gunther disease). *Eur J Pediatr*. 2005;164(2):104-107.

11. Faraci M, Morreale G, Boeri E, et al. Unrelated HSCT in an adolescent affected by congenital erythropoietic porphyria. *Pediatr Transplant*. 2008;12(1):117-120.

12. Martinez Peinado C, Diaz de Heredia C, To-Figueras J, et al. Successful treatment of congenital erythropoietic porphyria using matched unrelated hematopoietic stem cell transplantation. *Pediatr Dermatol*. 2013;30(4):484-489.

13. Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP. Congenital erythropoietic porphyria due to

a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. *Blood*. 2007;109(6): 2618-2621.

14. Shaw PH, Mancini AJ, McConnell JP, Brown D, Kletzel M. Treatment of congenital erythropoietic porphyria in children by allogeneic stem cell transplantation: a case report and review of the literature. *Bone Marrow Transplant*. 2001;27(1):101-105.

15. Taibjee SM, Stevenson OE, Abdullah A, et al. Allogeneic bone marrow transplantation in a 7-year-old girl with congenital erythropoietic porphyria: a treatment dilemma. *Br J Dermatol*. 2007;156(3):567-571.

16. Tezcan I, Xu W, Gurgey A, et al. Congenital erythropoietic porphyria successfully treated by allogeneic bone marrow transplantation. *Blood*. 1998;92(11):4053-4058.

17. Zix-Kieffer I, Langer B, Eyer D, et al. Successful cord blood stem cell transplantation for congenital erythropoietic porphyria (Gunther's disease). *Bone Marrow Transplant*. 1996;18(1):217-220.

18. Lagarde C, Hamel-Teillac D, De Prost Y, et al. [Allogeneic bone marrow transplantation in congenital erythropoietic porphyria. Gunther's disease]. *Ann Dermatol Venereol*. 1998;125(2):114-117.

19. Lebreuilly-Sohyer I, Morice A, Acher A, et al. [Congenital erythropoietic porphyria treated by haematopoietic stem cell allograft]. *Ann Dermatol Venereol*. 2010;137(10): 635-639.

20. Kauffman L, Evans DI, Stevens RF, Weinkove C. Bone-marrow transplantation for congenital erythropoietic porphyria. *Lancet*. 1991;337(8756):1510-1511.

21. Besnard C, Schmitt C, Galmiche-Rolland L, et al. Bone marrow transplantation in congenital erythropoietic porphyria: sustained efficacy but unexpected liver dysfunction. *Biol Blood Marrow Transplant*. 2020;26:704-711.

22. Zinter MS, Dvorak CC, Spicer A, Cowan MJ, Sapru A. New insights into multicenter PICU mortality among pediatric hematopoietic stem cell transplant patients. *Crit Care Med*. 2015;43(9):1986-1994.

23. Ged C, Moreau-Gaudry F, Richard E, Robert-Richard E, de Verneuil H. Congenital erythropoietic porphyria: mutation update and correlations between genotype and phenotype. *Cell Mol Biol (Noisy-le-grand)*. 2009;55(1):53-60.

24. de Verneuil H, Robert-Richard E, Ged C, Mazurier F, Richard E, Moreau-Gaudry F. [Successful gene therapy of mice with congenital erythropoietic porphyria]. *Med Sci (Paris)*. 2008;24(6-7):615-620.