Neonatal hemolytic anemia does not always indicate thalassemia: a case report
Al‑Harazi et al. BMC Res Notes
Neonatal hemolytic anemia does not always indicate thalassemia: a case report
Arwa A. Al‑Harazi 0 2
Bilguis M. Al‑Eryani 0 2
Butheinah A. Al‑Sharafi 1
0 Department of Pediatrics, School of Medicine and Health Sciences, Sana'a University , PO Box 700, Sana'a , Yemen
1 Department of Medicine, School of Medicine and Health Sciences, Sana'a University , Sana'a , Yemen
2 Department of Pediatrics, School of Medicine and Health Sciences, Sana'a University , PO Box 700, Sana'a , Yemen
Background: Congenital erythropoietic porphyria is a rare autosomal recessive disorder that affects heme‑ porphyrin synthesis. This disorder is due to the genetic defect of uroporphyrinogen III cosynthase. This defect results in the accumulation of high amounts of uroporphyrin I in all tissues, leading to clinical manifestations ranging from mild to severe chronic damage of the skin, cartilage and bone. Hypertrichosis, erythrodontia and reddish‑ colored urine are often present, as well as hemolytic anemia accompanied by hepatosplenomegaly. Case presentation: Here, we present a case of a 5‑ year‑ old male child of Middle Eastern origin who had been diagnosed as having alpha thalassemia and was undergoing chronic blood transfusions. He later presented with hypopigmented skin lesions and atrophy post‑ photosensitivity, persistent red‑ colored urine and hepatosplenomegaly. Laboratory investigations showed a high level of porphyrin metabolites in his plasma and erythrocytes. As a result, he was diagnosed as having Congenital erythropoietic porphyria. Conclusion: Here, we diagnose a case of congenital erythropoietic porphyria which was initially missed, although the clinical features were clear (red‑ colored urine, hepatosplenomegaly and hemolytic anemia were present since birth, and skin manifestations appeared at the age of 22 months after being exposed to sunlight). After a DNA test was performed, the patient was initially diagnosed as having alpha thalassemia. We identified two causes of hemolytic anemia (congenital erythropoietic porphyria and alpha thalassemia) in this patient. The diagnosis of congenital erythropoietic porphyria was missed up until the child turned 5 years old. To our knowledge, this is the first case of hemolytic anemia to be reported with a diagnosis of both congenital erythropoietic porphyria and alpha thalassemia.
Neonatal; Congenital erythropoietic porphyria; Alpha thalassemia; Case report; Hemolytic anemia
Congenital erythropoietic porphyria (Günther disease)
(CEP) is a rare autosomal recessive disorder that affects
the enzyme uroporphyrinogen III synthase. Its
clinical spectrum ranges from nonimmune hydrops fetalis
caused by severe hemolytic anemia in utero to late-onset
mild cases of light-sensitive cutaneous lesions that result
in mutilating scars in adults [
]. This enzyme defect leads
to the accumulation of type I isomer porphyrins. Those
are toxic, causing clinical manifestations that range from
mild to severe cutaneous photosensitivity, observed
starting at infancy and exhibited as mutilating skin
lesions. Furthermore, erythrodontia, chronic
hemolysis, splenomegaly, and massive porphyrinuria are also
]. The severity of the clinical
manifestations is markedly heterogeneous among the patients .
The outlook is favorable after bone marrow or stem cell
transplantation. Here, we report a case of a 5-year-old
boy who was treated as having thalassemia and who
presented later with hypopigmented skin lesions
post-sunlight exposure, along with persistent red-colored urine
A 5-year-old boy of Middle Eastern origin presented
to us with skin lesions, abdominal distension and
redcolored urine. He was the second child of a first-cousin
consanguineous marriage. The first child had died at
birth due to cord strangulation. Our patient was the
product of a full-term pregnancy without antenatal care;
delivery was normal, carried out at a hospital, and the
infant cried immediately after birth. His birth weight was
small (2200 g), and his head circumference was normal
(33 cm) with a wide anterior fontanel (10 × 7 cm). His
condition started at birth with poor and decreased
suckling activity, reddish urine and ecchymosis all over his
body. His coloration was pale with no bleeding, jaundice
or fever. Physical examination at that time revealed a
parasternal soft pansystolic murmur, splenomegaly located
6 cm below the costal margin (BCM) and a liver that was
palpable 2 cm BCM. The differential diagnosis included
hemolysis, metabolic diseases, septicemia, TORCH,
congenital leukemia and mucopolysaccharidosis (MPS). An
ophthalmological examination showed bilaterally
sloughing corneas, dry eyes, early lens opacity and bilaterally
hyperpigmented retinas. He was admitted to the
hospital and was treated as a case of neonatal septicemia; he
received antibiotics, multiple blood transfusion, and
l-thyroxine for 2–3 months. There was no improvement
in his symptoms and the family traveled abroad for
further investigations. The results of the complete blood
count and the thyroid function tests done at birth can be
seen in Table 1.
Other tests that were conducted included the following:
a blood smear, which showed normocytic normochromic
anemia; a normal osmotic fragility test; and a negative
Coombs test. Partial thromboplastin time (PTT),
prothrombin time (PT), liver and renal function tests were
also within the normal range. A TORCH screen was
negative; a bone marrow aspiration was normal with no
evidence of leukemia or myelofibrosis. An echocardiogram
revealed a perimembranous ventricular septal defect
(VSD). An abdominal ultrasound revealed huge
splenomegaly with a patent portal vein. A DNA study was also
done and revealed heterozygosity for alpha thalassemia,
which goes along with the diagnosis of having the alpha
thalassemia trait. Other tests performed ruled out
Gaucher’s Disease and MPS. The patient’s ammonia and
lactate levels were normal, while his serum ferritin level
was elevated (449 mg/ml). The results of a skeletal
survey were normal. The patient was managed with regular
blood transfusions (2–3 times per month) and an
ironchelating agent (Desferrioxamine).
At the age of 10 months, the patient exhibited an
increase in abdominal distension, with eruption of
brownish-stained teeth, while continuing to have reddish
urine. At the age of 22 months, he started developing
vesiculobullous skin lesions in sun-exposed areas (face,
hands and feet). The lesions left behind hypopigmented
areas upon recovery. At 30 months of age, and due to
improvement, blood transfusions were stopped,
however, the skin lesions progressed (Figs. 1, 2), and the red
urine (Fig. 4) and brown teeth persisted (Fig. 3).
Continued investigations showed elevated serum ferritin levels,
turbid urine with more than two proteins, elevated
urobilinogen levels, an RBC count of 10–12 cells/HPF, and
numerous WBCs. Furthermore, a culture of the urine
grew E. coli. To rule out other hemoglobinopathies that
cause hemolysis, we performed a hemoglobin
electrophoresis test that showed a result of Hemoglobin AA.
This meant that the patient had a normal hemoglobin
electrophoresis result and a normal hemoglobin as seen
in adults. At the age of 5, his condition progressed with
symptoms of worsening skin lesions and persistent red
urine and anemia. The patient came to our hospital for a
consultation, and we diagnosed him clinically as having
congenital erythropoietic porphyria. Tests were ordered
to confirm this diagnosis and revealed the following
results: Uroporphyrin I concentration = 28.1 mmol/
ml (normal value range is 0–4); Coproporphyrin I
concentration = 10.8 mmol/ml (normal value range is
0–6); Uroporphyrin I test in RBC = weakly positive; and
Heptacarboxyl porphyrin levels = 33.4 (normal value
range is 0–2). Although the presence of Heptacarboxyl
porphyrins is normally in line with a diagnosis of
hepatoerythropoietic porphyria (HEP) which has the same
clinical manifestations as CEP, it can also be present in cases
with CEP itself [
]. We relied in our diagnosis on the
clinical manifestations of the disease and on the presence
of uroporphyrin I and coproporphyrin I, which occur
only in CEP as a result of an absence of UROS
activity. Furthermore, erythrodontia and an elevated ferritin
serum levels are not features of HEP . Further
studies to detect the presence of mutations in the UROS and
GATA1 genes are needed to confirm the diagnosis, but
we were not able to perform these experiments due to the
unavailability of the tests in our country.
The final diagnosis for this case was congenital
erythropoietic porphyria. The mother was advised to keep the
patient away from the sun in order to avoid further
damage to his skin. The patient was prescribed frequent blood
transfusions, and was given a regimen of desferrioxamine
Congenital erythropoietic porphyria is an extremely rare
inborn defect affecting the metabolism of porphyrin
heme synthesis. Only several hundred cases have been
reported worldwide [
], and our knowledge, this is
the first case to be associated with the alpha thalassemia
trait. CEP is an autosomal recessive disorder affecting the
enzyme uroporphyrinogen III synthase, resulting in
clinical manifestations ranging from nonimmune hydrops
fetalis to a mild form of cutaneous photosensitivity
lesions in adult life [
]. Ocular manifestation includes
blepharitis, cicatricial ectropion, conjunctivitis, and
lagophthalmos with subsequent bilateral corneal scarring
occurring, eventually leading to blindness [
Alpha thalassemia is one of the world’s most common
single-gene disorders and is inherited as an autosomal
recessive disorder. It is commonly found in Africa, the
Middle East, India, Southeast Asia, Southern China,
and occasionally the Mediterranean region [
globin protein is made from four genes, two on each
strand of chromosome 16. A person with a deletion in
one of the alpha globin genes is said to be a silent carrier
of α-thalassemia, which generally does not cause
anemia. However, a person with a deletion in two α-globin
genes on the same chromosome (cis position) or on each
chromosome in the pair (trans position) is characterized
as having the α-thalassemia trait. This normally causes a
mild microcytic and hypochromic anemia that is often
mistaken with iron deficiency anemia. Whereas deletion
of three α-globin genes results in HbH disease, which is
enough to cause moderate to severe anemia, as well as
hepatosplenomegaly. The most severe form of the disease
is that resulting from the deletion of four α-globin genes
and is known as α-thalassemia major. Infants with this
condition develop hydrops fetalis syndrome and usually
die in utero or shortly after birth [
electrophoresis testing is not sensitive enough to diagnose
α-thalassemia, so PCR (polymerase chain reaction) and
restriction endonuclease tests may be used. These tests,
in addition to the DNA technology, can be diagnostic
]. The frequency range of alpha thalassemia alleles is
5–10% in the Mediterranean basin, 20–30% in portions
of West Africa, and as high as 60–80% in parts of Saudi
Arabia, India, Thailand, Papua New Guinea, and
Congenital erythropoietic porphyria can resemble
epidermolysis bullosa due to the occurrence of skin
blistering, scarring, and mutilation. Furthermore, it is also
important to exclude medication-induced
pseudoporphyria, which closely resembles CEP. Elevated
porphyrin levels in the urine, plasma, and stool will differentiate
CEP from these other conditions. Furthermore, in other
photodermatosis disorders, inflammation is not severe
enough to produce cutaneous blisters [
]. The presence
of erythrodontia is practically pathognomonic of CEP
]. CEP should be considered in all cases presenting
with cutaneous photosensitivity, red-colored urine and
blistering of sun exposed areas [
]. As observed in our
case, manifestations of CEP include bullous lesions on
photosensitive exposed areas, atrophic scars and
hypopigmentation, as well as erythrodontia [
]. In addition
to the clinical manifestations, the diagnosis can be
confirmed by observing the increase of the porphyrin
fraction in the plasma, urine and stool, as well as by genetic
Patient history and physical examination revealed the
presence of erythrodontia, skin blistering and
hypopigmentation, persistent red-colored urine, as well as
hemolytic anemia detected on a peripheral blood smear. The
investigations confirmed the presence of excess
porphyrins in the plasma. There is some correlation between
genotype and phenotype, and the severity of the
manifestations is usually associated with a C73R mutation,
a common form of CEP [
]. There have been reports of
x—linked CEP patients carrying a GATA1 mutation with
misleading hematological phenotypes that include
dyserythropoietic anemia, thrombocytopenia and
hereditary persistence of fetal hemoglobin [
]. Other modifier
genes could modulate the CEP phenotype. An example is
the ALAS2 gene mutation, which is the first and
rate-limiting enzyme of heme synthesis in erythroid cells [
patient had a severe form of hemolysis exhibited most of
the manifestations of CEP; however, genetic analysis was
not available. It is possible that the presence of this
mutation caused the severe deficiency of the enzyme
uroporphyrinogen III synthase and resulted in an increase in
uroporphyrin I and coproporphyrin I in plasma, red cells,
urine, feces, and in various tissues, explaining the
presentation in our patient. However, α-thalassemia was the
provisional diagnosis due to the presence of hemolytic
anemia and hepatosplenomegaly in the neonatal period.
This occurs in HbH disease and is a result of the deletion
of three α-globin chains. The genetic test did not give us
any details on the number of deletions on the alpha chain.
Alpha thalassemia is endemic to our region, and this
could justify the misdiagnosis. The co-occurrence of
alpha thalassemia and CEP in our patient is probably a
coincidence; however, as previously reported, an
interaction causing a more severe hemolytic anemia cannot be
ruled out [
Severe cases of anemia often require frequent blood
transfusions, and while this is sufficient to suppress
erythropoiesis and may be effective at reducing
porphyrin production and photosensitivity, it can result
in iron overload and other complications [
can explain the improvement in the symptoms of CEP
in our patient who was on frequent blood transfusions;
however, once he stopped the transfusions for a period
of time and was exposed to the sun, his symptoms
reoccurred. Protection from sunlight exposure, minimization
of skin trauma, and prompt treatment of any cutaneous
infections are highly important in managing CEP.
Sunscreen lotions and beta-carotene are sometimes
beneficial. Concurrent desferrioxamine treatment to reduce
iron overload, and hydroxyurea to suppress
erythropoiesis, may provide additional benefits. While splenectomy
reduces hemolysis and transfusion requirements in some
patients, and while oral charcoal may increase fecal loss
of porphyrins, both may be of little benefit in more severe
cases . A recent effort to rescue the common UROS
mutation (C73R) with a pharmacological chaperone and/
or a protease inhibitor has been reported [
]. At this
time, the most effective treatment is a bone marrow or
stem cell transplantation in early childhood, which
markedly reduces porphyrin and photosensitivity levels and
increases long term survival odds [
1, 11, 25
marrow transplantation was not performed for our patient
because of its unavailability in our country.
Alpha thalassemia is a common cause of neonatal
hemolytic anemia, and CEP is a rare genetic disease. Both
manifest with severe hemolytic anemia, hepatosplenomegaly,
and require frequent blood transfusions. The early
diagnosis of alpha thalassemia in our patient could have been
a factor in the delayed diagnosis of CEP, but persistent
red urine, post-sunlight hypopigmented atrophic skin
and erythrodontia should have been clues leading to an
earlier diagnosis of CEP.
CEP: congenital erythropoietic porphyria; MPS: mucopolysaccharidosis; BCM:
below costal margin; HEP: hepato‑ erythropoietic porphyria; UROS: uroporphy‑
AA treated the patient, wrote the manuscript, BAE shared in the care of the
patient and writing the manuscript, BAA helped with drafting and revising the
manuscript. All authors read and approved the final manuscript.
The authors have no acknowledgments.
The authors declare that they have no competing interests.
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