Haematological characteristics and spontaneous haematological recovery in Pearson syndrome

Pearson syndrome (PS), a rare multisystem mitochondrial disorder caused by single large-scale DNA (mtDNA) deletions (SLSMDs), commonly presents with anaemia in infancy.1, 2 Progressive multi-organ dysfunction such as lactic acidosis, pancreatic and renal dysfunction, failure to thrive endocrine disorders can develop during the course.1, 3 Interestingly, often resolves spontaneously; frequency prognostic impact of this observation is unknown. Patients PS have dismal prognosis, most patients die before age 5 years.3, 4 The few surviving into later childhood Kearns–Sayre syndrome. To date, ~100 cases been reported literature. Here we report on natural history 25 focussing haematological presentation. In referred between 1992 2019 our reference centre for undiagnosed cytopenias, diagnosis was suspected from cytology peripheral blood (PB) bone marrow (BM) cells, subsequently confirmed detection SLSMDs PB long-range polymerase chain reaction and/or Southern blots following informed consent.4-7 Three these had previously reported.5-7 Clinical data were collected retrospectively review medical charts documents. study approved Institutional Ethics Committee (University Freiburg, 325/20). Anaemia first clinical sign all diagnosed birth 31 months (median months). two-thirds (n = 17), only symptom at presentation suggesting that should be excluded infants hyporegenerative unclear aetiology. One-third 8) additional symptoms including 3), feeding difficulties 2), diarrhoea vomiting 1), intracerebral bleeding acidosis 3) or congenital malformations 1, omphalocele, oesophageal atresia dystopia). median initial haemoglobin level 63 (19−98) g/l (Table I). Mean corpuscular volume red cells F concentration increased 76% 80% respectively. Most also neutropenia thrombocytopenia. BM cellularity decreased nine 24 (38%) evaluated. These features resemble those other inherited syndromes. particular, Diamond–Blackfan shares common anemia infancy. Indeed, 10 present cohort severe erythroid hypoplasia. However, vacuolisation precursors ring sideroblasts noted 100% 70% respectively, led correct PS. Early course, required cell transfusions, received platelet transfusions. Subsequent spontaneous improvement transfusion independency both lineages observed 13 (cumulative incidence: 66%; Figure 1a, S1) generally occurred 1 years age. This has kept mind when considering possible indication haematopoietic stem transplantation (HSCT) due persistent cytopenia. None an allogeneic HSCT. Due high rate recovery potential risk irreversible organ damage chemotherapy prior HSCT transplant-related complications, not considered 3–4 years. outcomes five literature diverse; two died, one developed acute myeloid leukaemia recipient origin, alive 20 after respectively.8-11 mechanism remains obscure; it hypothesised positive selection HSCs harbouring low amount deleted mtDNA may occur course. Katada et al., 12 demonstrated mouse model proportion liver decreases Similarly, studies shown anaemia.13, 14 recent reports suggested clonal evolution chromosome 7 aberration, but any patient cohort.8, 10, 11 A wide spectrum non-haematological complications course (Figure 1b). suffered 19) muscle hypotonia 13). Pancreatic insufficiency 14) followed tubulopathy 8), 7), ophthalmological cardiac 5) 4). Neurological signs early included mild motor developmental delay 5). contrast, ataxia appeared Episodes associated infections documented patients. complexity dysfunctions underscores importance multidisciplinary team management 5-year overall survival 59% (95% confidential interval 37–81%) without reaching plateau (Fig 1c); died 49 (range: 15·3 years) [last follow-up (range) 32 (7–130) months]. cause death 9). Two respiratory infections, liver/renal failure, disease. There are currently no prediction factors outcome Unfortunately, there apparent treatment over time within decades. various similarly fatal 1c). Genotype–phenotype correlation controversial,4, 15 new conclusions drawn SI). interest shortest deletion [1500 base pairs (bp), identification number (ID) PSR11] lowest (50%, ID PSR10) late onset disease longer survival. prognosis lack effective therapy, patients, families physicians desperate find novel treatments, which alter New technologies therapy will hopefully open life-saving therapeutic window. authors thank their families, well treating physicians. acknowledge support Dr Ekkehard Wilichowski Göttingen, Germany), Elke Holinski-Feder (MGZ – Medizinisch Genetisches Zentrum, Munich, Germany) Ekkehart Lausch genetic analysis Miriam Erlacher, Brigitte Strahm van Buiren Kyogo Suzuki (Nagoya University, Nagoya, Japan) collection Mr Peter Nöllke statistical analysis. We would like Kaori Ishikawa Kazuto Nakada Tsukuba, Japan), Yu-ichi Goto (National Center Neurology Psychiatry, Tokyo, advice helpful discussions about Ayami Yoshimi Charlotte M. Niemeyer conceptualised designed study. Yoshimi, Sarah C. Grünert, Holger Cario, Aron Fisch, Ute Gross-Wieltsch, Kirsten Timmermann, Udo Kontny, Stephan Lobitz, Helen S. Odenthal, Irene Schmid, Barbara Uetz, Tanja Höll, Agnès Rötig, Thomas Lücke, Arndt Borkhardt, Gabriele Strauß, Alexander Hohnecker, Markus Metzler, Daniela Karall, contributed enrolment diagnostic procedures collections. drafted manuscript. All critically reviewed paper. Table SI. Mitochondrial landscape respect patient’s outcome. Fig S1. Haemoglobin (Hb) concentration, leukocyte count PSR8 recovery. Please note: publisher responsible content functionality supporting information supplied authors. Any queries (other than missing content) directed corresponding author article.