CLINICAL AND LABORATORY OBSERVATIONS
Pearson Syndrome in the Neonatal Period
Two Case Reports and Review of the Literature
Elena Maria Manea, MD,* Guy Leverger, MD,* Francoise Bellmann, MD,*
Popp Alina Stanescu, MD,w Adam Mircea, MD,* Anne-Sophie Le`bre, PhD,z
Agnes Rötig, MD, PhD,z and Arnold Munnich, MD, PhDz
Summary: Pearson syndrome is a multiorgan mitochondrial
cytopathy that results from defective oxidative phosphorylation
owing to mitochondrial DNA deletions. Prognosis is severe and
death occurs in infancy or early childhood. This article describes 2
cases with a severe neonatal onset of the disease. A review of the
literature reveals the atypical presentation of the disease in the
neonatal period, which is often overlooked and underdiagnosed.
Key Words: Pearson syndrome, neonatal
(J Pediatr Hematol Oncol 2009;31:947–951)
P earson syndrome (PS), a multi-organ mitochondrial
cytopathy, was originally reported as a disorder with
sideroblastic anemia, vacuolization of hematopoietic pre-
cursors, and exocrine pancreatic dysfunction.1 The main
characteristics of the disease, as described up to present, are
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. Prognosis is severe and death occurs in infancy or
early childhood owing to metabolic disorders and/or severe
infections.2 The disorder was shown to result from defective
oxidative phosphorylation and the patients were shown to
have mitochondrial DNA (mtDNA) deletions of varying
lengths and, in some cases, additional rearrangements
and duplications.3–5 The specific mtDNA deletion was
4.977 kbp long, deleting the complete genes for ATPases 6
and 8, cytochrome c oxidase III, NADH dehydrogenase 3,
4L, 4, and 5 and was associated with a 13 bp repeat. 3
The clinical onset of the disease is often overlooked in early
periods of life. The purpose of this article is to give a picture of
clinical and laboratory findings in the patients with neonatal
onset of the disease based on a review of the PS cases reported
in the literature. We also described the clinical evolution of
2 patients with neonatal PS with multiple organs’ involvement.
Received for publication October 21, 2008; accepted August 6, 2009.
From the *AP-HP, Hôpital Armand Trousseau, Department of
Pediatric Hematology Oncology and Université Pierre et Marie
Curie; zAP-HP, Hopital Necker - Enfants-Malades, Department of
Medical Genetics, Paris, France; and wAlfred Rusescu Institute,
Department of Pediatrics, Bucarest, Romania, Paris, France.
Reprints: Guy Leverger, MD, AP-HP, Hôpital Armand Trousseau,
Université Pierre et Marie Curie, UMRS 938, Paris 6, France
(e-mail: guy.leverger@trs.aphp.fr).
Copyright r 2009 by Lippincott Williams & Wilkins
J Pediatr Hematol Oncol  Volume 31, Number 12, December 2009
METHODS
Literature Review
We performed a PubMed search using the terms
‘‘Pearson syndrome’’ and ‘‘neonatal’’ for the period of 1979
to 2008 to identify relevant data on cases of PS reported in
publications in English and French. We reviewed PS cases
reported in the literature, selected those with neonatal onset
(up to 1 mo of age) and analyzed the clinical evolution,
mtDNA deletion, and the outcome of these patients.
Case Reports
Patient 1
A male patient was born after an uncomplicated preg-
nancy and delivery on term as the fourth child of healthy,
nonconsanguineous parents. The family history was unre-
markable. The parents and the older siblings were healthy.
He was born at term by cesarean section because of a severe
oligoamnios and had a birth weight of 2000 g (fifth percentile).
He was pale and edematous, hypotonic, had severe
respiratory failure, and tachycardia. Laboratory findings
revealed severe pancytopenia [hemoglobin (Hb) 3.8 g/dL,
7900 mm3 leukocytes with 48% neutrophils and 78,000 mL
platelets], marked metabolic acidosis (pH = 7.16) asso-
ciated with hyperlactacidemia (24 mmol/L), hypoglycemia
(1.8 mmol/L), hypokalemia (2.9 mmol/L), and hyponatre-
mia (140 mmol/L). Mechanical ventilation, circulatory
support, and several transfusions during the follow-up
period were realized. At 21 days of age, he still had anemia
[Hb 6.8 g/dL and medium corpuscular volume (MCV)
97.7 fl], neutropenia, and thrombocytopenia. The electro-
encephalogram performed at 2 days showed intermittent
rhythmic slow waves over the bilateral temporal areas, with
a similar aspect at 1 month. Magnetic resonance imaging at
16 days showed mild intraventricular hemorrhage and
myelinization abnormalities. A few days later, he developed
a severe inflammatory syndrome of unknown origin. The
bone marrow aspiration (BMA) performed at 4 months of
age revealed hypocellularity with erythroblastopenia (5%)
and marked vacuolization of bone marrow precursors. The
features were most consistent with a diagnosis of PS, which
was confirmed by genetic analysis of the mitochondrial
genome. A 9 kb deletion was detected in the patient’s
mtDNA from the bone marrow cells by polymerase chain
reaction and direct DNA sequencing as described by
McShane et al.5
Persistent pancytopenia was still found at 6 months.
At 6 months and 2 weeks of age, Haemophilus influenzae
pneumonia and severe sepsis occurred. At 1 year and 6
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Manea et al
months of age, he presented a developmental delay and
microcephaly (head circumference 42.5 cm, <3.5 SD) and
the visual evoked potential showed a disturbed trace with a
normal magnetic resonance imaging. Up to now he has a
good clinical and laboratory status without pancreatic or
hepatic dysfunction.
Patient 2
The male patient was born after an uneventful term
pregnancy from healthy unrelated parents. The parents and
the 3-year-old sister were healthy. The ultrasound examina-
tion 24 hours before delivery showed global heart enlarge-
ment, ventricular hypertrophy, and pericardial effusion. The
patient was delivered at 37 weeks gestation by emergency
cesarean section, with an APGAR score of 5, birth weight of
2460 g, and length of 46 cm. Immediately after birth, he was
pale and showed severe hypoplastic anemia (Hb 2.6 g/dL,
hematocrit 8%, and reticulocytes 0.3%), neutropenia
(10,200/mm3 leukocytes with 27% neutrophils), thrombocy-
topenia (116 000/mL platelets), metabolic acidosis (pH = 7.12),
and hypoglycemia (1.6 mmol/L). The necessary treatment
was given, with several transfusions in the first 3 days,
followed by a normalization of Hb, but with persistent
neutropenia (5400/mm3 leukocytes) and thrombocytopenia
(42,000/mL platelets) at the 13th day. The first BMA
performed at 17 days of age showed moderate hypocellu-
larity with granulocyte and erythrocyte precursors in all
stages of maturation. At the age of 1 month, he still had
anemia (Hb 7.2 g/dL). A second BMA, performed at 2
months of age showed normocellularity with mild erythro-
blastopenia with blockage of maturation, granulocytes
(54%) in all stages of maturation, micromegakaryocytes
and marked vacuolization of myeloid and erythroid
precursors, and features highly suggestive for PS. A 6 kb
deletion was detected in the patient’s mtDNA from the
bone marrow cells by polymerase chain reaction and direct
DNA sequencing.6
He had a good clinical evolution with a normal
physical and neurologic development and complete remis-
sion of cardiac hypertrophy at 2 months of age. At the age
of 3 months, he had moderate neutropenia and thrombo-
cytopenia and received 4 blood and 1 platelet transfusion.
No sign of pancreatic dysfunction or acidosis was reported.
At 4 months of age, he presented a normal blood count,
moderate cytolysis with cholestasis, lactic acidosis (lactate/
pyruvate ratio at 27), and mild aminoaciduria. Also, failure
to thrive with a small weight for his age and delay in
neurologic motor function. Now his clinical condition is
stable and no other signs of organic dysfunction appeared.
RESULTS
We reviewed 79 cases of PS reported in the literature,1–53
including our 2 cases and we analyzed the clinical features, la-
boratory findings, bone marrow aspirate, mtDNA (mtDNA)
deletion, and outcome of the patients with neonatal onset of
the disease (within the first month of life; Table 1).
The neonatal onset of clinical symptoms occurred in
33 out of 79 cases (41.8%; Table 2).
The most frequent symptom was a hyporegenerative
anemia (32 out of 33, 97%). Macrocytosis was reported in 6
cases at birth1,5,19,39,44,45 and a normalization of MCV in 6
cases: at 3 weeks,19,39,44 6,10 11,1 and 20 months.1 Anemia
was the only feature in 13 out of 32 cases (36.4%), associated
with leucopenia or thrombopenia in 10 cases (31.25%).
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J Pediatr Hematol Oncol  Volume 31, Number 12, December 2009
Anemia was associated with other symptoms in 12
cases: gastrointestinal (diarrhea, vomiting, hepatic, or
pancreatic dysfunction) in 5 (15.15%), neuromuscular
(tremor, hypo/hypertonia, and lethargy) in 4 (12%), and
metabolic (metabolic or lactic acidosis and hypo/hypergly-
cemia) in 3 cases (9%).
Six patients, including our reports (18.18%), had a
fulminate multiple organ involvement at birth,6,20,23,47 2 of
them presented with severe hydrops fetalis6,41 and 1 with
renal cysts and severe subjacent tubulopathy.20
One patient had neonatal cardiac involvement41 (from
3 cases with PS and cardiac dysfunction).19,22,41,42
Small birth weight was present in 21 out of 33 neonates
(63.64%), including our cases, and 3 patients had no other
clinical features of the PS at birth.6
The vacuolization of the hematopoietic precursors in
the bone marrow was present in the neonatal period in 8
patients (24.24%) and ringed sideroblasts in 4 cases
(12.12%). Medullar hypoplasia was found in 5 cases,
including 1 of our patients (15.15%) and ringed sideroblasts
as a unique feature at the BMA in 1 patient, with
vacuolization after the first month of life.
The 4.977 kbp mtDNA deletion (characteristic for PS)
accounted for 8 out of 33 cases of patients with neonatal PS
(24.2%) and for 10 out of 46 of the other cases of PS
(21.73%). Eighteen patients (54.5%) including our cases
had distinct deletions of their mitochondrial genome. The
genetic analysis was not reported in 6 cases (18%). Two
heteroplasmic point mutations have been described in a
patient with Pearson-like syndrome and heart abnormality.54
Directly repeated sequences were observed at the edges
of the deletions in 14 out of 33 neonatal patients (42.4%), a
common C nucleotide without repeats was detected in
1 patient35 and in 11 out of 33 (33%), the presence of
repeated sequences was not analyzed. Duplicated molecules
were associated to deletions in 2 patients19,24 and deletion-
dimers in 1 patient.12
The outcome was favorable for 15 out of 33 patients
(45.4%), which were alive at the end of the follow-up period.
Hematologic amelioration was noticed in 12 patients, with
persistence of thrombocytopenia (4),1,5,41,44 leucopenia (2)1,19
or bicytopenia (3),10,22,43 and complete remission concerning
all hematopoietic lines in 4 patients 22,46 (including our cases).
Five patients developed the Kearns-Sayre syndrome (KSS;
neuropathy, myopathy, external ophthalmoplegia, and pig-
mentary retinopathy),4,5,10,22 4 patients an exocrine pancrea-
tic disfunction,10,22,24,38,44,46 2 patients an insulin-dependent
diabetes mellitus,19,42,46 and 1 of them a complete heart
block.19,42
Eighteen out of 33 cases (54.5%) died, the majority
between 1.5 and 3.5 years (13 patients), 4 patients before 3.5
months, and 1 patient died at 14 days (Table 1). The causes
of death included sepsis, hepatic failure, cardiorespiratory
failure, and generalized hemorrhage.
DISCUSSION
There is clinical variability of PS onset, and anemia is
the most frequent symptom. Macrocytosis is a hallmark of
the disease and our analysis found a normalization of MCV
at different stages of age, although data are insufficient. Our
first patient showed a normal MCV at 21 days, which is
consistent with data in the literature.19,39,44
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J Pediatr Hematol Oncol  Volume 31, Number 12, December 2009 Pearson Syndrome in the Neonatal Period

TABLE 1. Characteristics of Patients With Pearson Syndrome in the Neonatal Period

Mitochondrial DNA Deletion/
Reference Clinical Features Enzyme Defect Outcome
1
Pearson et al Anemia, small birth weight — Death 26 mo
Anemia, small birth weight — Alive 3.5 y
Anemia, neutropenia, diarrhea, — Alive 3 y
irritability, small birth weight
Anemia, small birth weight — Death 29 mo
Rötig et al6 Anemia, hydrops fetalis, metabolic acidosis, 4.977 bp; 8482-13,460; ATPases 8 and 6, Death 25 mo
small birth weight COIII, ND3, 4L, 4, 5; repeats
McShane et al5 Anemia, lethargic, small birth weight 4.9 kb del; 8482-13,460; ATPases 8 and 6, KSS, alive
COIII, ND3, 4L, 4, 5; repeats 8y
10
Baerlocher et al Anemia, small birth weight 4.978 kb; 8469-13,447; ATPases 8 and 6, KSS, alive
COIII, ND3, 4L, 4, 5; repeats 8y
Superti-Furga Anemia, small birth weight, ketonuria, 6.34 kb del; 9238-15,576; COIII, ND3, IDDM,
et al12 failure to thrive, hypotonia 4L, 4, 5, 6, Cytb; repeats; dimer death 19 mo
Rötig et al4 Anemia 4.97 kb del; ATPases 8 and 6, COIII, Death 2 y
ND3, 4L, 4, 5; repeats
Anemia 4.97 kb del; ATPase 6, COIII, ND4, Alive 9 y
5; repeats
Pancytopenia, pancreatic dysfunction 4 kb del; 75% BM; repeats Death 3 mo
Anemia, diarrhea 5.9 kb del; tRNA gly, thr; repeats Alive 17 y
Anemia, metabolic acidosis 4 kb del; 57% leukocytes Death 2.5 mo
Smith et al,19 Anemia, fetal distress 77% BM, 64% del, 13% duplication IDDM,
Rahman and heart block,
Leonard42 alive 10 mo
Gürgey et al20 Anemia, small birth weight, vomiting, 3.5 kb del; ND5; 57% leukocytes Death 41 d
tubulopathy and glomerulosclerosis,
renal cysts, metabolic and lactic acidosis,
hypoglycemia
Kleinle et al21 Anemia, lactic acidosis, cholestasis 7.43 kb del; ATPase 6, COIII, ND3, Death 3 mo
4L, 4, 5, 6, Cytb; repeats
Muraki et al22 Anemia, small birth weight, hepatosplenomegaly 3.63 kb; 9337-12,974; COIII, KSS, heart
ND3, 4L, 4, 5 block, alive
16 y
Muraki et al,22,24 Anemia, small birth weight, metabolic acidosis, 3.15 bp del; 12,203-15,355; tRNA-His, KSS, alive
Sano et al38 hypoglycemia, hyperkalemia Ser, Leu; ND5, 6, Cytb; duplication 3 y
Muraki et al23 Pancytopenia, small birth weight, lethargic, pancreatic, 4.98 kb del; 10,559-15,548; Death 14 d
hepatic dysfunction, metabolic, lactic acidosis ND4, 5, 6, Cytb; repeats
Warris et al28 Anemia, small birth weight, premature 2.8 kb del; 80% blood Aspergillosis,
death 2 y
2 mo
Warris et al,28 Anemia, small birth weight, metabolic acidosis, 6.017 kb del; 7778-13,794; ATPases 8 Aspergillosis,
De Vries et al51 hyperglycemia and 6, COIII, ND3, 4L, 4; repeats death 16 mo
Morikawa et al35 Anemia, small birth weight 7.37 kb del; ATPase 6, COIII, ND3, 4L, Death 26 mo
4, 5, 6, Cytb
Gürakan et al37 Lactic acidosis, hypoglycemia, hypotonia 4.977 kb del; repeats Death
Lee et al39 Anemia, thrombocytopenia, vomiting 6 kb del; 7950-13,993; COII, ATPases 8 KSS, death
and 6, COIII, ND3, 4L, 4, 5 3 y 4 mo
Lichter-Konecki Anemia 4.977 kbp; ATPase 6, COIII, 3-MTG
et al40 ND4, 5; repeats acidosis,
death 3 y
1 mo
Li et al41 Pancytopenia, hydrops, cardiorespiratory insufficiency, 4.9 kb del; 8482-13,460; repeats; ATPases Alive 15 mo
small birth weight 8 and 6, COIII, ND3, 4L, 4, 5
Lohi et al43 Anemia, small birth weight 5.066 kb; 10,373-15,438 del; 80% Alive 9 mo
leucocytes
Demeocq et al44 Pancytopenia, hypotonia, small birth weight — Alive 26 mo
Stoddard et al45 Pancytopenia, small birth weight, failure to thrive — Death 54 d
Favareto et al46 Anemia, polypnea, hypertonia, tremor, hypoglycemia — IDDM,
death 19 mo
Anemia — IDDM, alive
* Pancytopenia, small birth weight, metabolic and lactic acidosis, 9 kb del; blood Alive 18 mo
cardiorespiratory insufficiency hypoglycemia, tremor
* Pancytopenia, small birth weight, metabolic acidosis, 6 kb del; blood Alive 4 mo
cardiac enlargement, hypoglycemia
*Index cases.
— indicates data not reported; BM, bone marrow; CO, cytochrome c oxidase; Cytb, cytochrome b; Del, deletion; Gly, glycine; His, histone; IDDM, insulin-
dependent diabetes mellitus; 3-MTG, 3-methylglutaconic aciduria; KSS, Kearns-Sayre syndrome; Leu, leucine; ND, NADH dehydrogenase; Ser, serine; Thr, threonine.

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Manea et al J Pediatr Hematol Oncol  Volume 31, Number 12, December 2009

The comparison of the general outcome of PS cases

TABLE 2. The Clinical and Biologic Features of the Patients With and that of neonatal PS showed little difference. Half of the
Pearson Syndrome in the Neonatal Period
patients with multiple organ involvement (including our
Clinical and Biologic Features No. Patients (%) reports) survived with complete improvement of hemato-
Onset symptoms logic parameters without disease progression. This suggests
Small birth weight 21 (63.64) that evolution is not related to the severity of the onset
Anemia 13 (36.4) symptoms at birth.
Leucopenia 9 (27.3) In conclusion, in most of the cases of PS, the
Thrombocytopenia 9 (27.3) symptoms are poor and quite atypical in the neonatal
Multiple organs involvement 6 (18.18) period, which makes it difficult to differentiate from an
Gastrointestinal 5 (15.5) infectious, neuromuscular, or digestive disease. Aplastic
Neuromuscular 4 (12)
anemia, associated with or without neutropenia or throm-
Metabolic (acidosis, hypo/hyperglycemia) 3 (9)
Bone marrow aspirate bocytopenia is a major symptom, which should be carefully
Vacuolization of the hematopoietic precursors 8 (24.24) investigated and the diagnosis of PS should be kept in
Hypoplasia 5 (15.15) mind, even if the clinical presentation does not evoke this
Ringed sideroblasts 4 (12.12) disease.
Molecular analysis
Common deletion (4.97 kbp) 8 (24.24)
Other deletions 18 (54.5)
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