Allogeneic bone marrow transplantation for Pearson's syndrome

Pearson's syndrome (PS) is a generalized mitochondropathy that occurs in infancy owing to a deletion or duplication of mitochondrial DNA (mtDNA).1 PS is characterized by hypoplastic macrocytic anemia alone or associated with thrombocytopenia or granulocytopenia, proximal tubular insufficiency, exocrine and endocrine pancreas insufficiency, failure to thrive, lactic acidosis with increased lactate/pyruvate ratio, urinary excretion of lactate and related organic acids, hyperlipidemia with liver steatosis and skin lesions.2 Prognosis is severe and death occurs in infancy or early childhood owing to metabolic disorders and/or severe infections. Neurological deterioration as a Kearns–Sayre syndrome3 usually appears in school-age children. Patients with hematological involvement receive support therapy but, currently, no specific treatment exists for PS.

We report a patient affected by PS with bone marrow (BM), renal and pancreas involvement, who received two unrelated donor hematopoietic stem cell transplantation (UD-HSCT).

PS was diagnosed in a 4-month-old female child with macrocytic anemia and mild hyperlactacidemia. A muscle biopsy confirmed a deficiency of the respiratory chain (III complexes) (Spectrophotometric analysis) and a large deletion (50%) of mtDNA (Southern blot analysis). During the following 5 years, the patient developed thrombocytopenia and neutropenia with recurrent bacterial infections. BM aspirate confirmed severe tri-linear hypoplasia and the presence of cytoplasm vacuolization in the myeloid precursors. No exocrine pancreas dysfunction was detected. Neuroradiological screening (magnetic resonance imaging-MRI) showed a mild hyperintensity of globi pallidi without any clinical symptom (Figure 1a and b). At the age of 7.5 years, the hematological involvement worsened. As no compatible family donor was available, an UD-HSCT was performed in order to treat the acquired BM aplasia. Conditioning regimen consisted of fludarabine (30 mg/m2 for 4 days), etoposide (400 mg/m2 for 3 days) and melphalan (100 mg/m2, on day −1). Graft-versus-host disease (GvHD) prophylaxis consisted of rabbit anti-lymphocyte serum (ATG, 2.5 mg/kg on days −4, −3, −2), low-dose methotrexate (10 mg/m2 on day +1, 8 mg/m2 on days +3, +6) and cyclosporine A (CSA, 3 mg/kg c.i. from day −7). She received a total of 4.5 × 108/kg unmanipulated BM nucleated cells. Three days after transplant, the patient developed pulmonary aspergillosis (Aspergillus fumigatus) treated with high doses of antifungal therapies (liposomal amphotericin B followed by voriconazole plus caspofungin), followed by surgical resection of the inferior right lobe of the lung. BM and peripheral blood (PB) STR-PCR analysis performed on day +60 revealed a decrease in the percentage of donor chimerism. Despite the discontinuation of CSA, a diagnosis of rejection was made. Three months later, the patient was reconditioned with thiotepa (2.5 mg/kg/day for 2 days) and cyclophosphamide (30 mg/kg/day for 4 days) and 7 × 108/kg mononuclear cells from the same donor were infused. GvHD prophylaxis consisted in ATG (2.5 mg/kg/day for 3 days) and CSA (3 mg/kg/day c.i. from day –7). Despite antifungal secondary prophylaxis, the day before HSCT the patient showed a relapse of fungal lung infection, which was treated with antifungal therapies (liposomal amphotericin B associated with caspofungin). She developed acute GvHD (aGvHD) treated with low and high doses of methylprednisolone associated with cycles of monoclonal antibody anti-CD25. She required insulin therapy for steroid-related hyperglycemia. On day +13, after diffuse muscle pain, she presented generalized seizures followed by lethargy, bradycardy and bradypnoea. Plasmatic and urinary metabolic investigations, chimical, cytological and microbiological analysis of cerebral spinal fluid (CSF) were normal. MRI showed hyper-intense signals in FLAIR sequences of both nuclei pallidi and cerebral cortex (Figure 1c and d). These findings suggested the presence of metabolic encephalopathy. Twenty days later, aGvHD improved as well as her neurological condition. Impairment of renal tubular function was documented, and bicarbonate supplementation was administered regularly. On day +160, MRI showed an almost completely resolved neurological picture with a mild persistent pallidum involvement (Figure 1e and f). Six months after second HSCT, to treat a chronic GvHD (cGvHD) resistant to steroids, anti-CD25, anti-CD20 and extracorporeal photo-chemotherapy and ameliorate tubular and pancreatic disorders father's mesenchymal stem cells (MSCs) were infused. The patient received two courses of father's MSCs given 12 weeks apart, the cellular dose was of 23 and 0.4 × 106/kg, respectively. One month later, cGvHD and proximal tubular function improved. MtDNA deletion was demonstrated by molecular analysis of urinary flaking cells (50%). On the contrary, mtDNA deletion was absent in the white blood cells, confirming complete resolution of hematological involvement. The STR-PCR sequence in the PB and in BM was regularly performed and showed a complete engraftment of donor cells. Twelve months after the second transplant, a BM aspirate demonstrated the occurrence of an acute myelogeneous leukemia (M0 FAB phenotype) of recipient origin. Cytogenetic study revealed a 7q deletion and trisomy 8. The patient died of progressive disease 22 months after the second HSCT.

Figure 1

Axial fluid-attenuated inversion recovery (FLAIR) MRI images. Study performed at the age of 7.5. (a) Mild hyperintensity of globi pallidi. (b) Normal cerebral cortex. Study performed 1 year later. (c) Increase of pallidal hyperintensity. (d) Diffuse cortical hyperintensity, resulting in a tram-track imagine. Study performed at the age of 9. (e) Faint residual hyperintense signal in the right globus pallidus. (f) Normal cerebral cortex signal intensity.

To our knowledge, this is the first case of PS in which the hematological manifestations completely disappeared after a successful allogeneic HSCT. However, the clinical course was extremely critical, and several complications occurred. Proximal tubular insufficiency, which was demonstrated in our patient by mtDNA deletion detected in urinary flaking cells, is a feature of PS.4, 5 Moreover, the drugs that were used to treat the infections and GvHD may have significantly contributed to renal and tubular damage. Pulmonary aspergillosis occurred both during the first and second HSCT. Patients affected by mitochondrial disorders are at greater risk of developing A. fumigatus infection owing to a dysfunction of the respiratory chain enzyme, which impairs the energy-demanding functions of the neutrophils, including chemotaxis, ingestion, degranulation and microbial killing.6 This could explain the severity and the early occurrence of fungal infection in our patient that led us to attempt many therapeutic strategies. It is well known that the neurological deterioration is a possible occurrence in patients affected by PS.3, 4, 5, 6, 7 The etiology of seizures and unconsciousness associated with magnetic resonance imaging (MRI) abnormalities occurred in our patient could be multifactorial. The bilateral lesions of nuclei pallidi could be related to a Kearns–Sayre syndrome. The MRI picture ameliorated during the follow-up, probably as consequence of improvement of her multisystemic involvement. Congenital BM failure syndromes with alteration of DNA repair are associated with leukemia8 but it is not known if PS has a potential capacity of malignant transformation. In our patient, the high doses of chemotherapies and the prolonged immunosuppressive treatments could have induced secondary oncogenetic anomalies in hematopoietic cells.

We conclude that allogeneic HSCT could be considered a possible therapeutic strategy for hematological disorders occurring in patients with PS especially in those without a severe multisystemic involvement of the underlying disease. We suggest careful pulmonary and neurological screening before transplant and close follow-up, in particular during the critical phases.


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This work was supported by the ‘Ministero della Salute – Ricerca Finalizzata Ministeriale’, ‘Fondazione CARIGE’, and ‘Compagnia San Paolo’.

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Faraci, M., Cuzzubbo, D., Micalizzi, C. et al. Allogeneic bone marrow transplantation for Pearson's syndrome. Bone Marrow Transplant 39, 563–565 (2007).

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