Hereditary Spherocytosis
Vasudha Mahajan, MD,* Sunil K. Jain, MD†
AUTHOR DISCLOSURE Drs Mahajan and Jain
have disclosed no financial relationships
relevant to this article. This commentary does
not contain a discussion of an unapproved/
investigative use of a commercial product/
device.
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Departments of *Pediatrics and †Neonatology, University of Texas Medical Branch,
Galveston, TX.
Abstract
Neonatal jaundice is commonly encountered in the neonatal period.
Although it is mostly asymptomatic, severe cases may present as
encephalopathy or kernicterus. Hereditary spherocytosis (HS) is the most
common cause of nonimmune hemolytic anemia and the third most
common cause of kernicterus after glucose-6-phosphate-dehydrogenase
deficiency and ABO isoimmunization. Awareness of the clinical presentation
and the laboratory tests necessary to diagnose the disease can lead to early
detection and effective interventions, thereby preventing adverse outcomes.
This article focuses on HS: its pathophysiology, clinical presentation in the
neonatal period, natural history, and the relevant diagnostic features of
evaluation.
Objectives After completing this article, readers should be able to:
1. Recognize the clinical signs of hereditary spherocytosis in different age
groups early.
2. Become familiar with the varied laboratory tests used to diagnose and
confirm hereditary spherocytosis.
3. Understand the natural history and complications of the disease, for
efficient follow-up.
4. Emphasize the protocol followed for prophylactic management: medical,
surgical, and immunization-related.
INTRODUCTION
Hereditary spherocytosis (HS) is the most common cause of nonimmune he-
molytic anemia due to an inherited red blood cell (RBC) membrane disorder
leading to mild to severe neonatal jaundice. The natural history of HS during the
neonatal period can involve mild to severe neonatal jaundice, leading to bilirubin-
induced encephalopathy or kernicterus. (1) In the USA Kernicterus Registry, 23
of 125 patients with kernicterus had hemolytic anemia, of whom 3 had severe
HS. The other common conditions leading to kernicterus were hemolysis sec-
ondary to ABO isoimmunization, glucose-6-phosphate-dehydrogenase deficiency,
and sepsis. (2) HS is characterized by spherical, doughnut-shaped RBCs in
Vol. 17 No. 12 DECEMBER 2016 e697
 the peripheral blood. HS is most commonly found in white PATHOPHYSIOLOGY OF HEREDITARY SPHEROCYTOSIS
patients of northern European ancestry, but can be seen
The RBC membrane is a dynamic and flexible structure that is
worldwide, with a prevalence of 1 in 2,000 to 5,000 births.
required for the RBCs to survive in the blood circulation. Al-
The inheritance is dominant in 75% of the cases, but some
though the main molecular defects in HS are heterogeneous,
cases of de novo mutations have also been reported. (3)(4)
the main common feature is weak vertical linkages of the
RBCs have various genes coding for membrane stability.
RBC cell membrane and lipid bilayer with the integral proteins.
HS is caused by defects in these genes, which lead to mem-
Quantitative or qualitative defects in 1 or more membrane
brane deformity and instability and subsequent destruction
proteins lead to RBC membrane instability. Various genetic
of RBCs while passing through the spleen, further leading
mutations have been identified in RBC membrane defects
to hemolysis and subsequent jaundice. (5)
leading to HS (Table 1). The vertical linkages include a spectrin,
b spectrin, ankyrin-1, band 3, and protein 4.2 interactions and
NORMAL RED BLOOD CELL MEMBRANE STRUCTURE lipid bilayer membrane interactions. When these interactions
are compromised, the cohesion between the bilayer and mem-
The RBC membrane is a dynamic and fluid structure that
brane skeleton is lost, which leads to destabilization of the lipid
allows RBCs to undergo deformations required for crossing
bilayer and release of skeleton-free lipid vesicles (Fig 2). (7)
vascular beds and to deliver oxygen. The specific structure
Two main pathways lead to the formation of spherocytes.
and organization of the various components that form the
The first pathway involves a defect in spectrin, ankyrin, or
membrane is responsible for its stability and deformability.
protein 4.2, which causes release of band-3–containing micro-
Any change in the structural organization can lead to a loss
vesicles. The second pathway involves a defect in band 3 it-
of function of RBCs and cause hemolytic disorders. (3)
self, leading to loss of band-3–free microvesicles from the cell
The RBC membrane consists mainly of a lipid bilayer
membrane. Both these pathways will result in the formation
(phospholipids and cholesterol) with embedded proteins
of spherocytes with reduced membrane surface area (mean
that constitute the membrane cytoskeleton. (6) Mature RBCs
corpuscular volume [MCV]), which cause destabilization of
cannot synthesize lipids, hence they depend on lipid ex-
the membrane and reduced deformability, which leads to
change and fatty acid acylation for repair and renewal. (6)
RBC damage in the spleen. (6) In a series of 300 cases of HS,
The phospholipid bilayer accounts for 50% of the weight of
(8) spectrin deficiency was the most common defect in those
the cell membrane. The core layer is hydrophobic and inter-
diagnosed in childhood, and band 3 defect was most com-
acts with the proteins. The protein layer consists of integral
monly seen in patients who were diagnosed in adulthood.
membrane proteins (band 3) and peripheral membrane pro-
These spherocytes are selectively damaged in the spleen.
teins (spectrin, protein 4.1; ankyrin, protein 4.2). The protein
(7) The spleen plays an important role in hemolysis of ab-
layer of RBC membrane is responsible for the antigenic,
normal RBCs with decreased deformability in HS. Phys-
mechanical, and transport properties of the RBC. Band 3 is
ical entrapment of RBCs in the splenic microcirculation,
the major integral protein and is responsible for the anionic
as well as phagocytosis, leads to destruction of deformed
transport and maintenance of protein-protein interactions.
RBCs. The splenic environment is very hostile to RBCs due
Band 3 also provides a binding site for glycolytic enzymes,
to low pH, glucose, and adenosine triphosphate, along
hemoglobin, and the skeletal proteins ankyrin, protein 4.1,
with increased free radicals, which contribute to RBC mem-
and protein 4.2. Spectrin consists of 2 subunits (a and b) and
brane damage (Fig 2). Some of these conditioned RBCs
is the major part of the RBC membrane skeleton. Spectrin
escape the splenic hostile environment and reenter the sys-
is very flexible, which is critical for normal RBC membrane
temic circulation. Destruction of spherocytes in the spleen
flexibility. Spectrin is linked to RBC membrane through
is the primary cause of RBC hemolysis in HS.
protein 4.1 junctional complex and through spectrin-ankyrin
interaction. Protein 4.1 is necessary for RBC membrane
INHERITANCE
stability and it interacts with spectrin, actin, and other pro-
teins of the RBC membrane. Lack of protein 4.1 will lead to In three-fourths of HS cases, the inheritance is autosomal
fragility of the RBCs and hemolysis. Ankyrin is a linkage dominant, and the rest are autosomal recessive or secondary
protein between spectrin and band 3. Protein 4.2 is a link to a de novo mutation. In autosomal recessive inheritance,
between the lipid bilayer, through its interactions, with an- the most commonly seen defect is in spectrin or protein 4.2.
kyrin and band 3S. The loss of linkages between the lipid Homozygous HS is reported very rarely, which can lead to
bilayer and the cytoplasmic skeleton composed of spectrin either fetal death or severe hemolytic anemia during the
leads to loss of surface area and spherocyte formation (Fig 1). neonatal period (Table 1).

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Figure 1. Diagram representing the erythrocyte membrane. The outer surface is separated from the inner proteins and structures by a lipid bilayer.
The protein defects involved in hereditary spherocytosis include band 3, ankyrin, spectrin, and 4.2.
CLINICAL PRESENTATION
During the perinatal period, the clinical spectrum of HS
ranges from asymptomatic neonates to severe fetal anemia
with hydrops fetalis. This wide range is because of various
genes and specific mutations involved, (2) presence of
coinherited conditions like mutations of genes involved
in hepatic bilirubin uptake (SLC01B1), or intrahepatic bili-
rubin conjugation (UGT1A1), which can increase the risk of
severe hyperbilirubinemia and kernicterus. (1)
Clinical HS is classified as mild, moderate, moderately
severe, and severe, based on the bilirubin, reticulocyte count,
and hemoglobin concentration (Table 2). The clinical presen-
tation varies, depending on the different age groups. (9) Infants
with a severe single membrane protein deficiency or an im-
balance with combined protein deficiencies (most commonly
band 3 and ankyrin defects) present with severe hemolysis.
(10) The clinical expression of HS is relatively uniform
within a given family, but the severity varies among families.
TABLE 1. Erythrocyte Membrane Genetic Defects Involved in Hereditary
Spherocytosis
PROTEIN INVOLVED (GENE) PREVALENCE (%)
Ankyrin-1 (ANK1) 40-65
Band 3 (SLC4A1) 20-35
b-spectrin (SPTB) 15-30
a-Spectrin (SPTA1) <5
Protein 4.2 (EPB42) <5
AD¼autosomal dominant; AR¼autosomal recessive.
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Clinically, the classic triad of anemia, jaundice, and spleno-
megaly is not common in neonates. More than 50% of
neonates with HS are not anemic during the first week after
delivery and splenomegaly is also rare. (4) The reticulocyte
count remains low relative to the severity of anemia because
of the sluggish erythropoietic response. (4) Spherocytes and
other biomarkers of hemolysis seen in older children, such
as decreased haptoglobin, are not seen in neonates. (10)
During the neonatal period, jaundice is the most com-
mon presentation and is seen in half of the infants with HS.
Phototherapy or even exchange transfusion may be required
to treat it. (10) The onset of jaundice is usually within the first
few days after delivery secondary to RBC hemolysis and the
inability of the immature liver to conjugate bilirubin. (4) Many
infants with HS escape detection in the neonatal period and
are diagnosed later after the onset of chronic hemolysis. In
neonates, the diagnosis of HS may be difficult because
the peripheral smear may not show typical spherocytes and
the osmotic fragility (OF) test is unreliable. RBC indices like
INHERITANCE DISEASE SEVERITY
AD, de novo Mild-moderate
AD Mild-moderate
AD, de novo Mild-moderate
AR Severe
AR Mild-moderate
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 Figure 2. Pathophysiology of hereditary spherocytosis. The primary defect is the deficiency in membrane surface area that may be produced by either
of these mechanisms. A. The density of the membrane skeleton is reduced due to defects of ankyrin, spectrin, or protein 4.2, which lead to
destabilization of the lipid bilayer and release of microvesicles. B. Defects in band 3 lead to band 3 deficiency and loss of its lipid-stabilizing effects. Both
mechanisms result in formation of spherocytes with decreased deformability. These erythrocytes become trapped in the spleen and undergo further
injury due to splenic conditioning.

mean corpuscular hemoglobin concentration (MCHC) and
MCHC/MVC ratio may be helpful when HS is suspected. (11)
Anemia
The hemoglobin is usually normal at birth but may deteri-
orate during the first 4 weeks after birth (3) because of
increased destruction and decreased erythropoiesis. (4)
Soon after birth, the splenic circulation develops fully,
leading to increased phagocytosis of the spherocytes by the
spleen. Secondly, a switch from fetal oxygenation via the
placenta to lung respiration results in increased oxygen
levels and consequent decreased erythropoietin secretion.
This is the reason that neonates rarely have reticulocytosis
of more than 10% despite having anemia. (5)(12) Erythrocyte
2,3-diphosphoglycerate (2,3-DPG) is also known to destabi-
lize the membrane by interfering with the spectrin and
4.1 complex linkages. (13) Fetal hemoglobin binds poorly to
2,3-DPG, which leads to an increased level of free DPG in
the blood. This increased DPG in the blood further weakens
the protein membrane linkages, thereby increasing RBC
membrane instability. During the first year, some neonates
with HS may be transfusion-dependent because of their
inadequate erythropoietic response to anemia. (4)
Family History
In any infant suspected to have HS, the initial assessment
should include a detailed history and physical examination
of the infant and detailed family history with particular
attention to anemia, jaundice, gallstones, and splenectomy
in any family member. Most cases (up to 75%) will have a
family history of HS. The common forms of HS are in-
herited in an autosomal dominant manner. This implies

TABLE 2. Classification of Hereditary Spherocytosis

MILD MODERATE MODERATELY SEVERE SEVERE

Hemoglobin (g/dL [g/L]) 11-15 (110–150) >8 (>80) 6-8 (60–80) <6 (<60)
Reticulocytes (%) <6 >6 >10 >10
Bilirubin (mg/dL [mmol/L]) 1–2 (17.1–34.2) 2 (34.2) 2–3 (34.2–51.3) >3 (>51.3)
Spherocytes – þ þ Micro spherocytes þ
OF (fresh blood) Normal [ [ [
Transfusions during infancy 0–1 0–2 >2 Regulara
Hereditary AD AD, de novo mutation AD, de novo mutation AR

AD¼autosomal dominant; AR¼autosomal recessive; OF¼osmotic fragility.

a
Patients depend on regular transfusions.

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that a child born with HS has a 50% chance of inheriting the
disorder from the parents. About two-thirds of infants with
HS have a parent with HS. (14)(15)(16) However, a positive
family history does not determine the severity of anemia
in the neonatal period. In the absence of a family history,
another important consideration in the differential diagno-
sis is autoimmune hemolytic anemia (ABO incompatibility,
Rh isoimmunization, or minor group incompatibility), which
can be excluded by means of a negative result on the direct
antiglobulin test (Fig 3).
Complete Blood Cell Count
Initial investigation of any infant suspected to have HS
should include a complete blood cell count along with RBC
indices, particularly MCHC and MCV. Peripheral smear
examination may be helpful and should be conducted in
all infants suspected to have HS (Fig 4). (17) However, up
to one-third of neonates with HS do not have spherocytes
on peripheral smear. The mean hemoglobin concentration
and reticulocyte count may be helpful in diagnosing HS,
along with family history and RBC indices. (18)
Splenomegaly
Most children and adults with HS have splenomegaly, but
other than assisting in the diagnosis, this is of little clinical
significance. The size of the spleen alone is not an indication of
the need for splenectomy. Splenomegaly does not increase
the chances of splenic rupture in patients with HS, and the
activity of children with HS should not be restricted. (9)
Red Blood Cell Indices
Christensen and Henry (11) found elevated MCHC values
(‡36.5) in infants with HS (98.2% sensitivity and 98%
specificity). Because infants with HS have low MCVs, the
ratio of MCHC to MCV (HS ratio) can be used to diagnose
HS. Yaish et al (19) found that a neonatal HS ratio greater

Figure 3. A. Approach for evaluating a neonate

with jaundice. B. Evaluating a neonate for possible
hereditary spherocytosis. BUBC¼bilirubin
unconjugated and conjugated; CBC¼complete
blood cell count; DAT¼direct antiglobulin test;
EMA¼epithelial membrane antigen;
G6PD¼glucose-6-phosphate-dehydrogenase;
HS¼hereditary spherocytosis; MCV¼mean
corpuscular volume; MCHC¼mean corpuscular
hemoglobin concentration.

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Figure 4. Peripheral smear in hereditary spherocytosis showing small
sized red blood cells lacking the central pallor.
than 0.36 was 97% sensitive and 99% specific and had a
99% negative predictive value to diagnose HS. The com-
bination of MCHC and RBC distribution width has very
high specificity (nearly 100%). (20) Reticulocytosis is vari-
able and usually not severe. Only one-third of infants with
HS will have reticulocyte counts greater than 10%. Simi-
larly, one-third of infants with HS will not have spherocy-
tosis on peripheral smear.
DIAGNOSTIC TESTS
Eosin-59 : Maleimide Binding Test
The epithelial membrane antigen (EMA) binding test uses
flow cytometry to determine if the amount of fluorescence
(reflecting EMA bound to specific transmembrane protein)
is derived from RBC. (21) The dye predominantly binds to
band 3 of the RBC membrane to evaluate protein confirma-
tion. The blood sample then undergoes flow cytometry and
the mean fluorescence intensity is measured. In HS, reduc-
tion in band 3 protein leads to decreased fluorescence in-
tensity. The cut-off value of the intensity above which it is
considered positive is debatable but the values range from
11% to 16% according to various studies performed. It is
quick and easy to use. This test is able to detect HS with a
sensitivity of 92.7% and specificity of 99.1%, with a positive
predictive value of 97.8%. (5)
The EMA binding test is the test of choice for the fol-
lowing reasons: 1) it requires a minimal amount of blood (5
mL), 2) the equipment required is easily available, 3) the test
results are available in 2 to 3 hours, 4) the blood sample can
be analyzed up to 7 days after sampling, 5) it may be used in
patients who have undergone recent transfusion because
the RBC gating process eliminates bias due to transfused
RBCs, and 6) the results of the test will be positive, irre-
spective of morphologic findings and age of the infant. The
limitations of this test are that it is less sensitive for HS
involving ankyrin defects or unknown molecular defects.
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Osmotic Fragility
OF is the degree of hemolysis that occurs when the RBCs
are placed under stress in a hypotonic solution. Normal RBCs
are biconcave and maintain osmotic equilibrium by taking
in the fluid when placed in hypotonic solution. In HS, the
RBCs have an altered membrane composition and a decreased
surface area–to-volume ratio. (3) This leads to a decreased
capacity of the RBCs to expand and easy rupture when placed
in a hypotonic solution. Compared with adult RBCs, neonatal
RBCs exhibit different responses to the osmotic stress. The
OF test has poor sensitivity and is unreliable in infants who
have received blood transfusions. About 25% of infants with
HS may display normal OF in their freshly drawn RBCs. (22)
After incubation at 37°C for 24 hours, RBCs of infants with
HS lose membrane surface area more readily. The incubated
OF test is considered the gold standard in the diagnosis of
HS. There are newer flow cytometry methods of assessing
RBC OF, which are showing promising results. (23)
Ektacytometry
Ektacytometry involves the use of a complex instrument
to help diagnose HS based on RBC shapes, viscosity of
the cytoplasm, and membrane deformability. (24) This test
needs a blood sample of only 100 mL. However, this test has
certain limitations: 1) difficult access to the instrument and
complex functioning requires specialized technicians, 2) the
blood sample may be analyzed up to 48 hours after sam-
pling, 3) its use is restricted soon after transfusion.
Genetic Testing
Confirmatory test for HS is done by sequencing of a rela-
tive’s genes. Genetic testing should be conducted in se-
vere cases of HS or for infants with HS with no family
history of HS. The aim of genetic testing is to provide
parents with genetic counseling regarding the recurrence
risk of HS in a subsequent pregnancy.
TREATMENT
Jaundice
The American Academy of Pediatric guidelines (25) should
be used in the management of hyperbilirubinemia. If in-
tense phototherapy is not enough to bring the bilirubin
concentration down, then exchange transfusion should be
used to avoid kernicterus. (26)
Anemia
Packed RBC transfusion should be given if the infant has
symptomatic anemia. Generally, blood transfusions are re-
quired up to age 1 year. Some infants with severe anemia in
utero or soon after birth remain dependent on blood trans-
fusions beyond 1 year of age. In view of the relatively poor
erythropoietic responses of infants with HS, recombinant
erythropoietin has been used with success during the first
few months after birth. (27) Infants with moderate to se-
vere HS should receive folate supplementation to increase
erythropoiesis.
Routine Observation and Frequency of Blood Tests
Patients should be closely observed for hematologic deteri-
oration during acute illnesses. Like children and adults,
infants with HS may also experience aplastic crisis. This is
more common after 6 months when maternally derived
antibodies have waned. Parvovirus B19-mediated bone mar-
row aplasia is commonly seen in children with HS. (28)
Parents should be provided anticipatory guidance regard-
ing the occurrence of hematologic decompensation with
viral illnesses. The wide spectrum of disease severity re-
quires individualized plans for follow-up visits to assess the
degree of anemia and to monitor growth and development.
Children who continue to require blood transfusion should
be closely monitored for iron overload.
Splenectomy
The spleen is the main site for destruction and phagocytosis
of RBCs. Splenectomy is highly beneficial in reducing hemo-
lysis by prolonging the lifespan of the RBCs. However, an
enlarged spleen is not the sole criterion for splenectomy. The
decision to perform splenectomy should be based on the
clinical severity of HS and associated gall stones. (5) It should
ideally be performed after the age of 6 years and before pu-
berty to prevent the severity of postoperative complications,
especially infections. (5) No particular approach is preferred
(laparotomy vs laparoscopic), and the decision is dependent on
the availability of skilled surgeons and the proper equipment.
If a child with HS is undergoing splenectomy for symp-
tomatic cholelithiasis, the gall bladder should also be re-
moved to decrease recurrence. (29)
The risk of infection with encapsulated organisms like
Neisseria, Streptococcus pneumoniae, Meningococcus, and Hemo-
philus influenzae type b is highest in the first few years after
splenectomy and is more severe in younger children. (29) Life-
long postoperative prophylaxis with penicillin is recom-
mended, but there is no evidence to support its efficacy.
(29) Patients should get routine vaccinations, including pneu-
mococcal vaccinations, every 5 years. However, there is no
consensus regarding the need, frequency, and type of reim-
munization. (5) The risk of thrombosis in patients with post-
splenectomy HS is the same as that in the general population
and routine anticoagulation is not recommended. (5)(29)
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COMPLICATIONS
Cholelithiasis
The formation of bilirubin gall stones is a common com-
plication of HS. According to a large retrospective study,
6% to 16% of the affected patients develop symptomatic gall
stones, with most occurring after age 10 years. (30) Patients
with coexisting Gilbert syndrome have been shown to have a
higher risk of cholelithiasis. (30)
Aplastic Crisis
Asymptomatic HS may manifest as aplastic crisis in child-
hood associated with parvovirus B19 or influenza infec-
tion. (29) The patient presents with fever, maculopapular
rash, and severe anemia that may warrant a transfusion.
This crisis may last from 10 to 14 days.
CONCLUSIONS
All pediatricians taking care of neonates and children
should know the presentation, diagnosis, and treatment
of HS. In all neonates presenting with significant jaundice,
a careful review of family history of jaundice, evaluation of
RBC indices (MCV, MCHC, MCHC/MCV ratio >0.36), and
interpretation of peripheral blood smear may be all that is
required to diagnose HS. Rarely, erythrocyte EMA binding,
incubated OF, or flow cytometric detection of RBC OF may be
helpful. During the first week after birth, in an infant with
hemolytic jaundice, bilirubin monitoring and treatment are
required. For all cases of diagnosed HS, hemoglobin moni-
toring is required during the first 6 months.
If clinicians suspect HS early, establish the diagnosis,
provide appropriate treatment, and offer anticipatory guid-
ance to the parents, adverse outcomes can be avoided.
American Board of Pediatrics
Neonatal—Perinatal Content
Specifications
• Know the role of the spleen in normal host defenses
• Know the consequences, clinical manifestations, and
management of altered spleen function, including asplenia
• Know the etiology and pathophysiology of hemolytic anemias in
the neonate
• Know the clinical and laboratory features of hemolytic anemia in
the neonate
Vol. 17 No. 12 DECEMBER 2016 e703
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 Hereditary Spherocytosis
Vasudha Mahajan and Sunil K. Jain
NeoReviews 2016;17;e697
DOI: 10.1542/neo.17-12-e697

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 Hereditary Spherocytosis
Vasudha Mahajan and Sunil K. Jain
NeoReviews 2016;17;e697
DOI: 10.1542/neo.17-12-e697

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/17/12/e697

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