Results
A male neonate born at 40w4d via spontaneous vaginal delivery presented
to the neonatal intensive care unit (NICU) at 38-hours-old with
hyperbilirubinemia on phototherapy. His vital signs showed a blood
pressure was 54/31 mmHg, pulse of 140 beats/minute, body temperature of
37.2°C (99°F), respiratory rate of 70 breaths/minute, and oxygen
saturation of 99% on room air. The patient’s head circumference,
length, and weight were all within one standard deviation of average for
his age range and sex. Physical examination revealed diffuse jaundice
and scleral icterus. Both of his parents identified as African American,
and his family history was negative for hemoglobinopathies and hemolytic
anemia.
His lab work was notable for a total bilirubin of 20.2 mg/dL (normal
range, 0-8.2), direct bilirubin of 0.4mg/dL (0.0-0.6), hemoglobin of
17.2 g/dL (14.7-18.6), mean corpuscular hemoglobin concentration (MCHC)
of 26.0 g/dL (31-34.2), mean corpuscular volume of 98.6fL (97.3-109.8),
red cell distribution width of 21.9% (12.0-15.2), and a reticulocyte
count of 9.2% (2.5-6.5). These findings in combination with the
patient’s jaundice on exam and down trending hemoglobin to 12.9 g/dL
suggested a hemolytic process. The differential diagnosis focused on
both intrinsic and extrinsic causes of hemolytic anemia, including
membrane defects, enzyme deficiencies such as G6PD and pyruvate kinase
deficiencies, hemoglobinopathies, as well as autoimmune
diseases.2
On consultation with the pediatric hematology-oncology team, additional
labs were suggested, revealing a negative Coombs test and no ABO or Rh
incompatibility. He was found to have a G6PD Quantity of 22.1
U/g[Hb] (7.0-20.5) and a Pyruvate Kinase Enzyme Activity of 11.9
U/g[Hb] (5.5-12.4). Additionally, a hemolytic anemia screening panel
was ordered on day of life (DOL) 6. This panel revealed increased
osmotic fragility, decreased Eosin 5-Maleimide binding, and decreased
Protein band 3, suggesting a membrane-related disease, such as HS or
hereditary elliptocytosis (HE).
Peripheral blood smears were also used to investigate the cause of the
patient’s symptoms. A smear from DOL 2 showed polychromasia with
normocytes, occasional spherocytes, and rare schistocytes in the absence
of bite or helmet cells. White blood cells (WBCs) and platelets showed
normal morphology. At this point, the differential included HS or HE, as
the smear was significant for spherocytes on blood smear, and the
patient had reticulocytosis in the absence of an immune cause. HS and HE
can present similarly on peripheral smears early in life although they
have different disease courses to prepare for.3
The patient was discharged in stable condition from the NICU after 8
days with daily outpatient folic acid and vitamin D3. He continued to
have significant reticulocytosis and indirect hyperbilirubinemia.
Because of the persistently abnormal lab values, the negative family
history, and with a goal of determining the underlying cause and
inheritance risk in her siblings and in his own offspring, a NGS panel
was ordered.
The patient was evaluated using a Hereditary Hemolytic Anemia Panel,
which revealed a heterozygous out-of-frame deletion in Exon 2-3 of theSPTB gene, resulting in an abnormal and non-functioning spectrin
protein product. Loss-of-function mutations of the SPTB gene are
known to cause abnormally shaped erythrocytes and are implicated in both
HS and HE.4 However, the specific deletion present in
this patient has not been reported in literature and is thus potentially
pathogenic.
A repeat peripheral smear performed at 10 months of age showed RBC
morphology as normocytic, normochromic with significant polychromasia.
Numerous spherocytes with occasional acanthocytes and echinocytes were
noted. WBCs and platelets had a normal appearance (Fig. 1). This
confirmed a diagnosis of HS, specifically moderate-severe HS. The
patient had hemoglobin between 6-8, as well as a reticulocyte count
between 6-10%.5 Additionally, the parents were
offered a NGS test to discover if this is a de novo or an inherited
mutation.