Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 393-397
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Natural history of hereditary spherocytosis during the first year
of life
F. Delhommeau,
T. Cynober,
P. O. Schischmanoff,
P. Rohrlich,
J. Delaunay,
N. Mohandas, and
G. Tchernia
From the Laboratoires d'Hématologie et de Biochimie,
Hôpital Bicêtre, Assistance Publique
Hôpitaux de
Paris, et Faculté de Médecine Paris XI, Le
Kremlin-Bicêtre; Service de Pédiatrie Hématologique,
Hôpital R. Debré, Assistance PubliqueHôpitaux de
Paris, Paris; and Lawrence Berkeley National Laboratory, Berkeley, CA.
 |
Abstract |
Although hereditary spherocytosis (HS) is a common disorder of the
red cell membrane, its clinical and biologic expression at birth and in
early infancy has received little attention. In order to obtain
insights into the natural history of HS during infancy, we studied 46 neonates, 39 from families in which 1 of the parents had previously
been given a diagnosis of HS and 7 presenting with nonimmune hemolytic
anemia and no family history of HS. Of these 46 neonates, 23 were subsequently confirmed to have HS and 23 were found to be
healthy. The hematologic and biologic analyses carried out in this
cohort of 46 newborns enabled us to develop guidelines for early
diagnosis of HS. A careful clinical follow-up of 34 HS patients during
the first year of life allowed us to define several important clinical
features of HS during this period. Hemoglobin values are usually normal
at birth but decrease sharply during the subsequent 20 days, which
leads, in many cases, to a transient and severe anemia. The
anemia is severe enough to warrant blood transfusions in a large
number of infants with HS (26 of 34 in our series). The aggravation of
anemia appears to be related to the inability of these infants to mount
an appropriate erythropoietic response to anemia and to the development
of splenic filtering function. These findings indicate that careful
monitoring of infants with HS during the first 6 months of life is
important for appropriate clinical management.
(Blood. 2000;95:393-397)
© 2000 by The American Society of Hematology.
| |
Introduction |
Hereditary spherocytosis (HS) is a common inherited
hemolytic anemia involving cell-membrane alterations. Its prevalence in northern Europe is approximately 1 in 2000.1,2 Its clinical expression is heterogeneous, ranging from severe transfusion-dependent anemia to clinically silent forms with well-compensated chronic hemolysis. Because some patients, even those who later manifest either
mild or moderate forms of the disease, can present with a very severe
phenotype in early infancy, a reliable strategy for diagnosis of HS in
neonates is needed. Well-defined criteria for diagnosis of HS at birth
have not been firmly established. In fact, the disease is diagnosed in
only one third of affected infants during the first year of
life.3 Moreover, the natural history of the disease during
the first year of life has received little attention.4,5 In
order to fill these gaps in our understanding of HS, we undertook a
study with the following goals: (1) to develop objective criteria for
diagnosis of HS at birth, and (2) to describe the natural history of
the disease during the first year of life.
Detailed biologic and hematologic evaluations of blood samples from 46 neonates with a presumptive diagnosis of HS enabled us to establish
criteria for diagnosis of HS at birth. We found that in neonates, as in
adults, a decrease in the surface area of the red cell membrane and
increased red cell dehydration were hallmarks of HS. A careful clinical
follow-up of a cohort of 34 HS patients during the first year of life
enabled us to define several important clinical features of the disease
during this period. Hemoglobin (Hb) values that were normal at birth
decreased sharply during the subsequent 20 days, which led, in most
cases, to a transient and often severe anemia. The anemia was severe enough to warrant blood transfusions in 26 of the 34 infants. During
the first year of life, erythropoiesis increased and, by the age of 1 year, most of the children had well-compensated chronic hemolysis and
no further need for blood transfusions. These findings indicate that
children with HS have a severe phenotype early in life and that careful
monitoring of infants with HS during the first 6 months of life is
important for appropriate clinical management.
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Patients and methods |
The criteria for diagnosis of HS at birth were established on the
basis of a study of 46 blood samples from neonates suspected of having
HS. These samples were sent to our laboratory by various obstetric and
pediatric services in order to confirm or rule out a diagnosis of HS.
Samples from neonates in whom a diagnosis of HS was suggested by
familial history or the presence of icterus or anemia were assessed by
osmotic gradient ektacytometry6 and red blood cell indices,
as previously reported.7-9 Infants with associated other causes of neonatal hemolysis, such as isoimmune hemolytic anemia, as
well as infants with a gestational age < 38 weeks, were
excluded from the study.
Complete blood counts and red blood cell indices (mean corpuscular Hb
concentration [MCHC], red cell volume distribution width [RDW], Hb
concentration distribution width [HDW], and percentage of hyperdense
cells) were obtained at the time of diagnosis by using an automated
hematology analyser (H*2, Bayer Diagnostics, Tarrytown,
NY).10 Reticulocyte counts were obtained with an automated
hematology analyzer (H*3, Bayer Diagnostics) or by manual counting of
reticulocytes on blood smears after staining with new methylene blue.
Red cell deformability measurements were performed with an osmotic
gradient ektacytometer (Bayer Diagnostics).8 Controls were
age-matched healthy newborns or infants. Red cell membrane proteins in
blood samples from probands and other affected family members were
analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis,
as previously described.11,12
To delineate the natural history of HS during the first year of life,
we selected 34 patients with HS (from 26 families) who were available
for regular follow-up, including 23 patients with a dominant mode of
inheritance. For these 23 infants, either a parent or a
close relative with HS had undergone splenectomy. Twenty-one patients
with HS born between 1980 and 1992 were entered into the study
retrospectively; the other 13 were entered into the study
prospectively. Statistical analysis was performed with the unpaired
Student t test.
| |
Results |
Neonatal diagnosis
Detailed hematologic and red cell analyses were performed on blood
samples from 46 neonates. Thirty-nine of these infants were from 31 families in which a parent had previously received a diagnosis of HS.
The other 7 neonates had nonimmune hemolytic anemia but no familial
history of HS. The analyses were carried out in either cord blood
samples (15 infants) or venous blood samples (31 infants) drawn during
the first month of life. The osmotic deformability profiles of the
blood samples are illustrated in Figure 1A.
These profiles clustered into 2 distinct groups on the basis of the
maximum value attained by the deformability index (DImax).
The first group of osmotic deformability profiles precisely matched the
deformability profiles obtained with blood samples from healthy adults
and children, whereas the second group had features similar to those
obtained with blood samples from adults with HS. The DImax
values for the first group of blood samples (23 of the 46 samples) fell
within the normal range for normal adult red cells, whereas those for
the second group (23 of the 46 samples) were significantly lower
(Figure 1B). Because the DImax value provides a direct
measure of mean membrane surface area of red cells,6 these
findings indicate that the group of blood samples with decreased
DImax values contained red cells with reduced surface area,
a hallmark of spherocytosis.
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| Fig 1.
Hematologic and red cell analyses in hereditary
spherocytosis (HS).
(A) Osmotic gradient ektacytometric profiles of blood samples. The
deformability profiles of red cells from nonaffected newborns span the
dotted area, whereas those of red cells from newborns with HS fall
within the hatched area. DImax indicates
maximum deformability index, a measure of red cell surface area;
and Omin, the osmolality at which the deformability value
reaches a minimum in the hypotonic region of the gradient, a measure of
osmotic fragility of red cells. There is a decrease in DImax
values (B) in children with HS, reflecting membrane surface-area
loss, and a right shift of the deformability curve in the hypotonic
region (Omin), reflecting a decreased ratio of surface area
to volume in the HS red cells (increased osmotic fragility) (C). Solid
diamonds indicate affected children; and open diamonds, nonaffected
children. The percentage of hyperdense cells (cell hemoglobin (Hb)
concentration > 410 g/L) (D), mean corpuscular hemoglobin
concentration (MCHC) (E), and hemoglobin concentration distribution
width (HDW) (F) are higher in HS. In contrast, there is a large overlap
between red cell volume distribution width (RDW) in newborns with HS
and that in nonaffected newborns (G). The range of normal values in
adults and children (B and C) or age-matched newborns (E-G) is
indicated by dotted lines. The normal threshold value for percentage of
hyperdense cells is indicated by the dotted line in D.
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We identified 23 HS infants with a decreased surface area of red cell
membranes (DImax < 0.39) in the cohort of 46 infants screened. Of the 23 blood samples from this group, 17 showed a shift to
the right of the hypo-osmolar point (Omin) in the osmotic deformability profile (Figure 1C), indicating that the red cells had
increased osmotic fragility, a distinct feature of spherocytes. But, in
contrast to our findings with respect to reduced surface area, the
increase in osmotic fragility was not a consistent feature of all HS
blood samples: 6 of the 23 infants with HS had normal osmotic
fragility. As has been documented of red cells in adults with HS, red
cells in the newborns with HS were dehydrated.
Increased percentages of hyperdense cells (> 4% of red cells with a
cell Hb concentration > 410 g/L) were noted in 20 of the 23 newborns with HS (Figure 1D). Interestingly, an increased percentage of hyperdense cells was a feature of blood samples from 5 of the 6 HS
patients whose red cells had normal osmotic fragility, whereas increased osmotic fragility was a feature of blood samples from 2 of
the 3 HS patients who did not have an increased percentage of
hyperdense cells. MCHC was elevated (> 335 g/L) in 19 of the 23 HS
newborns (Figure 1E), and HDW was increased (> 34.5 g/L) in 20 (Figure 1F). In contrast, there was a noticeable overlap in the RDW
values in blood samples from healthy newborns and those from newborns
with HS (Figure 1G). All these cellular features were reconfirmed on
repeated assessment of blood samples obtained a year later from infants
given a diagnosis of HS, as well as samples from those considered not
to have HS.
HS during the first year of life
Thirty-four infants with HS (including 13 of the 23 given a
diagnosis of HS at birth), from 26 families, were monitored regularly during early childhood and the following characteristics observed.
Clinical features.
The main clinical features observed during the first months of life
were pallor, dyspnea (mild difficulties in breathing while feeding), or
both, related to anemia in 31 of the 34 infants and to neonatal icterus
in 27. Neonatal icterus occurred early in most patients (bilirubin
level ranging from 168 to 462 µmol/L during the first 3 days of life)
and led to phototherapy in 24. Splenomegaly was noted within the first
6 months of life in 23 of the 34 infants (range, 1-45 weeks; median, 5 weeks).
Hb values.
In 26 patients with HS who did not have a transfusion, one or several
Hb measurements were available during the first month of life. At birth
or during the first 96 hours of life, the mean Hb value was 150 g/L
(range, 117-196 g/L) in the 19 newborns from whom samples were
obtained. Hb values were above the normal threshold of 146 g/L in 63%
of these infants and ranged from 117 to 142 g/L in 37%, suggesting
anemia. Surprisingly, Hb values at birth were not statistically
different from those in normal cord-blood samples or samples from
nonaffected age-matched infants (Table 1).
However, in the affected babies from whom samples were obtained after
the age of 5 days, Hb values fell below the normal range (Figure
2A). A similar pattern of Hb values was
noted in all infants with HS, irrespective of initial clinical
presentation. This decrease persisted throughout the following weeks,
resulting in Hb levels < 80 g/L during the first month of life in
75% of the children (Figure 2B).
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Table 1.
Hemoglobin values at birth in healthy full-term
newborns and in newborns with hereditary spherocytosis (HS)
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| Fig 2.
Changes in Hb values.
(A) Temporal evolution of Hb values in 3 infants who did not have
transfusions during the first weeks of life. Shaded area shows the
range of Hb values in healthy infants.13 B shows histograms
of Hb values (mean ± SD) before the first transfusion in infants
with HS, as a function of postnatal age. The number of infants with HS
(n) evaluated at various postnatal ages is indicated (a: n = 19; b:
n = 12; c: n = 10; d: n = 8).
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Reticulocyte counts.
Serial reticulocyte counts were available for 18 of the 34 infants with
HS. In 16 of the 18, reticulocyte counts were increased at birth, as is
observed in normal newborns.13 Interestingly, however,
subsequent reticulocyte counts decreased below the threshold value of
200 × 109/L and remained low for several weeks to
months. During this period, erythropoiesis did not
compensate for the low Hb values. Reticulocyte counts increased
progressively with age, however, and by the time the infants reached 1 year of age, the counts were again > 200 × 109/L,
resulting in better compensation for hemolysis. A representative example of the evolution of the reticulocyte response in an infant with
HS is shown in Figure 3. Analysis of the
reticulocyte data showed an inverse relation between transfusion
requirements and reticulocyte counts 
200 × 109/L
(Figure 4). Among 18 HS newborns for whom
sequential reticulocyte counts were available, 15 required blood
transfusions. Over time, 12 of these 15 infants became transfusion
independent, whereas the 3 other infants remained transfusion dependent
(3, 7, and 10 transfusions, respectively, during the first year of
life) in spite of having reticulocyte counts persistently above
200 × 109/L. Clearly, in these 3 infants, the
increased reticulocytosis was unable to compensate for increased red
cell destruction.
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| Fig 3.
Temporal evolution of Hb values and reticulocyte counts
in a patient with recurrent transfusion-dependent anemia in early
infancy.
Arrows indicate transfusions; dotted line, Hb values; and solid line,
reticulocyte counts.
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| Fig 4.
Inverse relation between reticulocyte count at least
200 × 109/L and transfusion requirements in infants
with HS.
Dotted line indicates reticulocyte count at least
200 × 109/L; solid line, transfusion requirements.
Although sequential reticulocyte counts were available for 18 infants
with HS, only 15 of these patients required transfusions during the
first year of life.
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Red cell-membrane defects.
Red cell-membrane protein analyses were performed in either probands or
other affected members of 17 families (25 patients). Eleven families
presented with combined ankyrin and spectrin deficiency (probably
reflecting a mutation of the ANK1 gene), whereas 6 other families presented with isolated spectrin deficiency (most likely reflecting a mutation in the SPTB gene). Four infants born into 3 HS families with band 3 deficiency during the course of this study
were found to be unaffected by HS.
Transfusion requirements.
Of the 34 infants studied, 26 (76%) required transfusion therapy
during the first year of life. Fourteen of the babies had several
transfusions, whereas 12 received a single transfusion. A high
bilirubin level associated with anemia required an
exchange transfusion at the age of 2 days in 3 of the 26 infants. The
first transfusion was prescribed during the initial 2 months of life in
24 (92%) of the 26 infants. The Hb values at which a first transfusion
was prescribed varied widely; however, red blood cell transfusions were
always prescribed when Hb values decreased below 100 g/L by the age of
8 days and below 85 g/L thereafter. Of the 24 children who required red
cell transfusions during early infancy, only 8 continued to need
transfusions between the ages of 6 and 12 months. A follow-up of 3 to 5 years showed that 6 of these 8 infants with HS remained transfusion
dependent and underwent subtotal splenectomy14 between 2 and 5 years of age. The 2 others, who did not require splenectomy,
received a single transfusion because of a pure red cell aplasia due to
parvovirus B19.
| |
Discussion |
The increased rate of red cell destruction and the ability of
erythropoiesis to compensate for this destruction are the 2 processes
that determine the clinical severity of chronic hemolytic anemias. At
birth and during the first month of life, major readjustments occur in
both these processes. On the one hand, the splenic circulation is fully
developed only after birth,15,16 resulting in an enhanced peripheral destruction of circulating abnormal red blood cells such as
spherocytes. Consequently, hemolysis that is likely to be quiescent or
mild in fetuses affected by HS (except in the very severe
forms)17,18 increases dramatically after birth as the
splenic microvascular filtration and phagocytosing function become
fully effective. On the other hand, erythropoiesis, though highly
stimulated during fetal life, abruptly enters a hypoplastic phase
shortly after birth. The primary physiologic mechanism responsible for
decreased erythropoiesis is a dramatic reduction in erythropoietin secretion, which is probably related to both the switch from hepatic to
renal erythropoietin secretion and the marked elevation in oxygen
levels resulting from the transition from fetal to lung respiration.19 A newborn with HS thus has to cope with both an increased rate of red cell destruction and an abruptly restricted ability to mount an appropriate erythropoietic response. Together, these 2 deleterious effects markedly aggravate anemia in patients with HS during the neonatal period and early infancy. The neonatal period has also been reported to be critical in murine models of HS,
and it has been shown that neonatal transfusions can extend the
lifespan of spectrin-deficient ja/ja pups.20
Our study of infants with HS during their first year of life highlights
3 facts: (1) a reliable diagnosis of HS can be made at birth, (2) there
is a dramatic postnatal decrease in Hb values, and (3) an adequate
reticulocyte response cannot be mounted for several months, which leads
to a requirement for transfusion therapy that, in most cases, is transient.
In regard to the reliable diagnosis of HS in newborns, documentation of
a decreased membrane surface area in red cells by osmotic gradient
ektacytometry is the best indicator of spherocytosis, as previously
reported for HS in adults. When osmotic gradient ektacytometry is not
available, judicial assessment of data from different laboratory tests,
including the osmotic fragility test (with a comparison to an
age-matched control); red cell indices, particularly the percentage of
hyperdense red cells; red cell morphologic evaluations; and careful
assessment of family history can confirm most cases of HS in infants.
It should be emphasized, however, that decreased membrane surface
area is a hallmark of spherocytes of various origins and may also be
transiently observed in acquired spherocytosis related to immune
hemolytic anemia. Therefore, when HS is suspected at birth, it is
important to test for maternal-fetal incompatibility. Repeated
documentation of persistent cellular abnormalities, including decreased
surface area, an increased osmotic fragility, and an increased
percentage of hyperdense red cells, will confirm a diagnosis of HS,
whereas the recovery of normal cellular features will be consistent
with a diagnosis of immune hemolytic anemia.21
Our finding of near-normal Hb values at birth and a subsequent dramatic
decrease in Hb levels during the first weeks of life (between days 5 to
30) in infants with HS is of major clinical relevance and has not
previously been emphasized. This finding highlights the need for both
an early and reliable diagnosis of HS and a careful follow-up in
affected children. In infants considered to be at risk for HS, a normal
Hb value at birth should not be used to rule out the diagnosis of HS or
disregard the need for regular monitoring of hematologic status during
the first weeks of life. Finally, a satisfactory erythropoietic
response leading to well-compensated hemolysis, as indicated by
persistently high reticulocyte counts and transfusion independence, was
observed in most children only after several months of life. Moreover, the time it took to develop an appropriate erythropoietic response varied markedly from individual to individual.
On the basis of our findings, 4 groups of patients could be
retrospectively defined in terms of transfusion requirements. The first
group could be cared for without transfusions during the first year of
life, despite low Hb values during the initial follow-up. Twenty-four
percent of the patients in our study belonged to this group. For such
patients, regular follow-up is mandatory until a trend toward an
increase in reticulocyte counts leading to an acceptable Hb level can
be documented. The second group of patients (34% of the total) needed
only a single transfusion and, in most instances, this transfusion was
administered before the age of 2 months. The third group (24% of
patients) needed several transfusions and reached sustained transfusion
independence only at an age ranging from 4 to 9 months. The fourth
group required continuous transfusion support until a splenectomy was
performed; 18% of our patients belonged to this group with severe
forms of HS. Our findings regarding transfusion dependency are similar to those in an Italian pediatric survey.5
No reliable prognostic criteria for predicting transfusion requirements
during infancy in patients with HS emerged from our study. Family
history was not useful in predicting the severity of anemia in the
infant. However, it appeared that in all children who required
transfusion, the Hb value decreased by > 3 g/L per day after birth
and during the first 3 weeks of life. Because of the small size of
our patient population, no definite conclusion can be drawn,
but our data strongly suggest that whenever HS is diagnosed in
neonates, the evolution of Hb and reticulocyte values should be
monitored carefully every other day during the first 10 days of life.
Anemia at birth, or an abrupt decrease in Hb values during the first
weeks of life, is a likely predictor of future transfusion needs. There
appears to be a critical need to develop reliable predictive criteria
for the transfusion needs of infants with HS. Alternative
clinical management strategies to decrease or avoid
transfusions during the first months of life in anemic
infants should also be explored.22
| |
Acknowledgments |
We are grateful to J. A. Chasis for many helpful discussions and to M. Dehan for help in preparing the manuscript.
| |
Footnotes |
Submitted May 7, 1999; accepted September 20, 1999.
Supported by a grant from Direction de la Recherche Clinique, AP-HP,
Paris (CRC 96082) and a grant from the National Institutes of Health (DK26263).
Reprints: Narla Mohandas, Mailstop 74-157, Lawrence Berkeley
National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720; e-mail:
mnarla{at}lbl.gov.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction
