Late recurrence of congenital erythropoietic porphyria symptoms after initial remission post-bone marrow transplant

Dear Editor,

In 2012, Singh S et al. published a case letter titled “Bone marrow transplantation improves symptoms of congenital erythropoietic porphyria even when done post puberty.”¹ They reported a post-pubertal boy with congenital erythropoietic porphyria (CEP), which improved significantly after allogeneic bone marrow transplantation (BMT). This boy, lost to follow-up, returned 18 years after the transplant. As one of the few centres in the country performing allogeneic BMT for non-malignant indications like CEP, we feel it is important to raise awareness about the long-term clinical course post-transplant. At age 14, this patient underwent allogeneic BMT after a low-dose cyclophosphamide-based myeloablative regimen from his human leukocyte antigen (HLA)-matched, unaffected sibling [Figure 1]. The symptoms began improving after BMT and continued to do so for 1.5 years before stabilising.

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Figure 1:

Mild facial hypertrichosis and healing blisters at the time of transplant.

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He showed around 50% improvement in his clinical symptoms, loss of fluorescence of urine and stool, and normalisation of haemoglobin despite the post-pubertal transplant. But after 6 years of transplantation, he started to notice a progressive increase in the severity of the various symptoms. Although the symptoms were progressively getting worse, he perceived an overall less than baseline disease activity for about 12 years, after which it became the same as baseline. He developed shortening of fingers and toes due to recurrent blistering and progressive acro-osteolysis and mutilation of the nose and ears over the last few years [Figure 2]. On his recent visit, his teeth and urine showed reddish fluorescence on wood lamp examination [Figure 3]. The qualitative spectrophotometric analysis for porphyrins was positive in both urine and plasma with a peak at 620 nm. The quantitative levels were also significantly high (>300 µg/mmol). Because of the substantial physical disfigurement and disability resulting from the disease, he was dissatisfied with the outcome of the BMT [Supplementary Figure]. Figure in supplementary file A psychiatric consultation led to a diagnosis of moderate depression.

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Figure 2:

Marked facial skin infiltration, nasal distortion, and scarring post-18 years of transplant.

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Figure 3:

Urine at recent presentation showing reddish fluorescence on wood lamp examination.

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CEP is a rare autosomal recessive disorder caused by uroporphyrinogen III synthase (UROS) enzyme deficiency. This further causes an accumulation of porphyrins in the haemopoietic system and skin. CEP can have variable phenotypic presentations but is characterised by cutaneous photosensitivity, intravascular haemolysis, and tissue mutilation. To date, the only curative treatment considered is BMT, but long-term data on post-BMT patient outcomes are unavailable.² Available reports have been compiled in Table 1. BMT replaces bone marrow cells that are UROS-deficient with ones producing the haem group, reducing the production of porphyrins. Based on other inborn errors of metabolism, BMT should be performed early in the patient’s life before frank iron overload and marked symptoms set in.³ Most cases reported in the literature showed no clinical signs of CEP after a successful BMT, except for erythrodontia, which persisted, even without the use of strict photoprotection measures.^4,5 Reasons for the failure of BMT in our case are unclear but can be multifactorial such as possible mixed chimerism (not tested in our case), reduced-intensity conditioning regimens which may have led to high remainder marrow erythropoietic activity with insufficient myeloablation, greater phenotypic severity, older age at BMT, pre-BMT comorbidities and possibly persistent porphyrin production in nonerythroid tissue such as the liver. Similar failure of BMT as in our case has been reported 20 years after transplant, evidenced by blistering of the skin on the hands and face after sun exposure, erythrodontia and hypertrichosis, and significant elevation of total porphyrins, all consistent with recurrence of CEP.⁶ However, this case had undergone BMT at 2 years of age. This emphasises that BMT failure after initial success may be independent of the age of the patient at the time of transplant. It is important to assess for chimerism in the recipients after engraftment when BMT is done for haematological indications. High persistent recipient erythrocytes can convey insufficient myeloablation even though mixed chimerism can be enough for clinical benefit in enzymatic disorders.⁷ Long-term surveillance is required to ascertain the definitive causes of BMT failure and methods to prevent them. This case underscores the potential for recurrence of initial disease severity after BMT in a case of CEP after an initial marked improvement and also broadens our knowledge that BMT done at a later age and milder preprocedural conditioning might be associated with a risk of eventual failure.