# Successful treatment of congenital erythropoietic porphyria using matched unrelated hematopoietic stem cell transplantation in an adult: A case report

Pierre Peterlin, Julia Bonnelye, Alice Garnier, Amandine Le Bourgeois, Thierry Guillaume, Maxime Jullien, Hervé Dutartre, Marie Le Moigne, Caroline Schmitt, Laurent Gouya, et al.

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## To cite this version:

Pierre Peterlin, Julia Bonnelye, Alice Garnier, Amandine Le Bourgeois, Thierry Guillaume, et al. Successful treatment of congenital erythropoietic porphyria using matched unrelated hematopoietic stem cell transplantation in an adult: A case report. Skin Health and Disease, 2024, 4 (2), pp.e342. 10.1002/ski2.342. hal-04753355

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## CASE REPORT

SKIN HEALTH AND DISEASE
Open Access

# Successful treatment of congenital erythropoietic porphyria using matched unrelated hematopoietic stem cell transplantation in an adult: A case report

Pierre Peterlin<fnref n="1" />,<fnref n="2" /> ID | Julia Bonnelye<fnref n="3" /> | Alice Garnier<fnref n="1" /> |

Amandine Le Bourgeois<fnref n="1" /> | Thierry Guillaume<fnref n="1" />,<fnref n="2" /> | Maxime Jullien<fnref n="1" /> |

Hervé Dutartre<fnref n="3" /> | Marie Le Moigne<fnref n="3" /> | Caroline Schmitt<fnref n="4" /> | Laurent Gouya<fnref n="4" /> |

Antoine Poli<fnref n="4" /> | Sebastien Barbarot<fnref n="3" /> | Patrice Chevallier<fnref n="1" />,<fnref n="2" />

### Correspondence

Pierre Peterlin.

Email: pierre.peterlin@chu-nantes.fr

### Funding information

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors

### Abstract

Congenital erythropoietic porphyria (CEP), or Gunther disease, is a rare genetic disease responsible for severe dermatologic, hepatic and/or haematological damages related to the deficient activity of the uroporphyrinogen III synthase. Allogeneic stem cell transplantation (Allo-SCT) represents the only curative treatment and few allotransplanted cases have been reported in children but not in adults. Here we report for the first time the successful cure of a 46-year old man with CEP with a 5-year follow-up after Allo-SCT.

## 1 INTRODUCTION

Porphyrias are a rare group of metabolic disorders caused by the deficient activity of a specific enzyme in the heam biosynthetic pathway.<fnref n="1" /> Among porphyria, the congenital erythropoietic porphyria (CEP), also known as Gunther disease, is the rarest porphyria, with a prevalence estimated at 1 or less per million individuals per year. This congenital autosomal recessive disease is most often due to homozygous or compound heterozygous mutations in the UROIIIS gene on chromosome 10. Genotype/phenotype relationships have been reported, with, for example, increased phenotype

severity in carriers of the C73R mutation. Germline mutations in the X-linked erythroid-specific transcription factor GATA 1 have been also reported. Mutations in these genes lead to a reduction in erythrocyte UROIIIS enzyme activity (<1--10% of the normal), responsible for an accumulation of toxic I-isomer porphyrins. The depth of the enzyme deficiency modulates the level of porphyrin accumulation and the severity of the disease. Porphyrins first accumulate in erythroid precursors, then are released in plasma by haemolysis, diffuse and accumulate in tissues, mainly in skin and bone marrow but also in liver and dentin.<fnref n="1" /> Porphyrins are eliminated in urine and faeces. Clinical manifestations begin at

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2024 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

<footnote n="1">¹Clinical Hematology, Nantes University Hospital, Nantes, France</footnote>

<footnote n="2">²Equipe 12 CRCI2NA - INSERM UMR1307, CNRS UMR 6075, CRCINA IRS-UN, University of Nantes, Nantes, France</footnote>

<footnote n="3">³Dermatology Department, Reference Center for Cutaneous Porphyrias, Nantes University Hospital, Nantes, France</footnote>

<footnote n="4">⁴Reference Center for Rare Diseases Porphyrias, Louis Mourier Hospital, AP-HP, Colombes and Research Center of Inflammation, UMR1149 INSERM, Université de Paris, Paris, France</footnote>
<figure><img src="image_3.png" /><figcaption>**FIGURE 1** Cutaneous lesions of the ear and the hand before (on the left) and after (on the right) the allograft.</figcaption></figure>

in Figure 1. Pain has disappeared, sclerotic skin lesions reduced with no discomfort anymore. Photosensitivity disappeared and the patient is now able to swim and to wear t-shirt. ‘It’s a new life!’, as he said. The patient is now considered cured of his disease and has a normal life that he can share with his wife and his two daughters.

3 | DISCUSSION AND CONCLUSION

ASCT have been reported for the first time for CEP in 1991 by Kauffman et al⁵ in a 10-yo female who received a bone-marrow graft from an HLA-identical sibling donor. This patient unfortunately died from cytomegalovirus infection after transplant but an encouraging haematologic response was documented. Since then, multiple other paediatric cases have been published showing the efficacy of ASCT to cure CEP.²,⁴,⁶⁻¹⁵ Interestingly, a tandem sequential liver transplant and Allo-SCT from the same haploidentical donor has been reported in a child with CEP, this strategy allowing for discontinuation of immune suppression.¹³ This highlights the potential role of Allo-SCT in patients needing solid transplant to avoid prolonged immunosuppression,

risk of infection, or rejection by inducing tolerance of the transplanted solid organ.

In adults, acquired erythropoietic porphyrias secondary to myeloid malignancy, especially myelodysplastic syndrome, are well identified in adults. These patients were found to have normal erythrocyte UROsynthase activity, and no constitutive UROIIIS or GATA1 mutations.¹⁴ The success of Allo-SCT has been reported in only one adult with such acquired CEP secondary to a myelodysplastic syndrome with chromosome 3 alterations.¹⁵ Conversely, no Allo-SCT for CEP in adults has been reported so far.

Porphyrin levels of our patient remain above the normal range at distance of Allo-SCT, reflecting the porphyrin production by non-erythroid tissues. Indeed, UROIIIS deficiency is still present in non-erythroid tissues (for example liver cells) and can lead to a persistent accumulation of porphyrins despite full replacement of erythroid tissues with HSCT as shown by the erythrocyte porphyrins chromatography. Other studies have described a similar situation.⁴,¹² As reported here, plasma porphyrin levels remain below a clinically relevant threshold and did not to impair major clinical improvement of skin lesions.
<table><caption>TABLE 2 Erythrocyte porphyrins chromatography.</caption><thead><tr><th rowspan="3">Date</th><th rowspan="3">Total porphyrin levels in erythrocyte N &lt; 1.9 µmol/L erythrocyte</th><th colspan="8">High performance liquid chromatography</th></tr><tr><th>Protoporphyrin IX</th><th>Harderoporphyrin</th><th>Coproporphyrin</th><th>Pentacarboxyporphyrin</th><th>Hexacarboxyporphyrin</th><th>Heptacarboxyporphyrin</th><th>Uroporphyrin</th></tr><tr><th>N: 64%-92%</th><th>N: 0%-5%</th><th>N: 5%-16%</th><th>N: 0%</th><th>N: 0%-2%</th><th>N: 0%-4%</th><th>N: 0%-7%</th></tr></thead><tbody><tr><td>Before transplant 01/02/2016</td><td>41.1</td><td>8.8</td><td>0.9</td><td>15.5</td><td>4.0</td><td>5.6</td><td>6.1</td><td>59.1</td></tr><tr><td>Day+ 67 post-transplant *05/07/2017</td><td>4.5</td><td>80.2</td><td>6.5</td><td>4.7</td><td>0.0</td><td>0.0</td><td>0.0</td><td>8.6</td></tr><tr><td>5 years post-transplant*11/02/2022</td><td>0.65</td><td>71.1</td><td>0.0</td><td>18.6</td><td>0.0</td><td>0.0</td><td>0.0</td><td>10.3</td></tr></tbody></table>

In conclusion, to our knowledge, this is the first reported and successful case of Allo-SCT in an adult with CEP. This suggest that Allo-SCT should be considered in children with non-severe CEP showing progressive aggravation of the disease at adult age. Allo-SCT can lead to a significant improvement in skin signs, even in patients with major complications due to a long course of the disease. Of course, the decision must be balanced with the risks of complications related to bone marrow transplantation. However, it has to be kept in mind that CEP is generally associated over time with devastating and irreversible lesions.

## ACKNOWLEDGEMENTS

Not applicable.

## CONFLICT OF INTEREST STATEMENT

None to declare.

## AUTHOR CONTRIBUTIONS

**Pierre Peterlin:** Conceptualization (lead); investigation (lead); methodology (lead); resources (lead); writing—original draft (lead). **Julia Bonnelye:** Writing—review and editing (equal). **Alice Garnier:** Writing—review and editing (equal). **Amandine Le Bourgeois:** Writing—review and editing (equal). **Thierry Guillaume:** Writing—review and editing (equal). **Maxime Jullien:** Writing—review and editing (equal). **Herve Dutartre:** Investigation (equal); writing—review and editing (equal). **Marie Le Moigne:** Writing—review and editing (equal). **Caroline Schmitt:** Investigation (equal); writing—review and editing (equal). **Laurent Gouya:** Investigation (equal); methodology (equal); supervision (equal); writing—review and editing (equal). **Antoine Poli:** Writing—review and editing (equal). **Sebastien Barbarot:** Investigation (equal); supervision (equal); writing—review and editing (equal). **Patrice Chevallier:** Conceptualization (equal); investigation (equal); supervision (equal); writing—review and editing (equal).

## FUNDING INFORMATION

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

## DATA AVAILABILITY STATEMENT

The data underlying this article will be shared on reasonable request to the corresponding author.

## ETHICS STATEMENT

Not applicable.

## ORCID

Pierre Peterlin https://orcid.org/0000-0001-5463-6686
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How to cite this article: Peterlin P, Bonnelye J, Garnier A, Le Bourgeois A, Guillaume T, Jullien M, et al. Successful treatment of congenital erythropoietic porphyria using matched unrelated hematopoietic stem cell transplantation in an adult: a case report. Skin Health Dis. 2024;4(2): e342. https://doi.org/10.1002/ski2.342