CLINICAL CHEMISTRY
Single Case Report
Congenital Atransferrinemia
A Case Report and Review of the Literature
RANDY L. HAMILL, M.D., 1 JOSEPH C. WOODS, M.D., 1 AND BRUCE A. COOK, M.D. 2
A four-year-old Polynesian girl with a two-year history of severe
microcytic, hypochromic anemia (which was refractory to iron
therapy) had a decreased beta-globulin fraction on serum protein
electrophoresis, resulting from the absence of the transferrin
(TRF) band. Subsequent assays for TRF showed a level below
the detectable range. Liver biopsy revealed significant deposition
of hemosiderin within hepatocytes and Kupffer cells, in addition
to early fibrosis. Two bone marrow aspirates were hypercellular,
with decreased myeloid-erythroid ratios. This case represents
the eighth reported example of congenital atransferrinemia, a
rare, apparently autosomal recessive disease. (Key words: Congenital atransferrinemia; Anemia; Hemosiderosis; Therapy) Am
J Clin Pathol 1991;96:215-218
Congenital atransferrinemia (CAT) is an extremely rare,
recessively inherited disorder. To date, only seven cases
have been reported in the world literature. Transferrin
(TRF) is a glycoprotein with a single polypeptide chain
and a molecular weight of approximately 90,000 daltons,
that mediates the transfer of hemoglobin iron and absorbed iron to cells and storage sites.1 Patients who have
CAT or acquired atransferrinemia (AT) have moderate
to severe microcytic, hypochromic anemia, with normal
serum iron levels, high serum ferritin values, and a significantly low total iron-binding capacity (TIBC). Intestinal iron absorption continues, and iron overload can be
expected to develop in all patients. We report an additional
case of CAT in a four-year-old Polynesian girl from
American Samoa, along with the literature on this topic.
crocytic anemia, which had required transfusion therapy on at least three
occasions. She had been given iron several times without benefit. About
three weeks before her transfer to Honolulu, the child was seen in the
Pediatric Clinic of another institution in Pago Pago, American Samoa.
At that time, she was febrile, with mild respiratory symptoms. She also
had significant hepatosplenomegaly. A complete blood count was performed, and her hemoglobin level was 40 g/L (4.0 g/dL). She received
transfusions of whole blood, and, subsequently, she was transferred to
our hospital. When she arrived, additional history was obtained from
her mother, who denied a family history of anemia. Additionally, the
patient's mother stated that the child had no known history of blood
loss and that multiple tests to detect blood in the stool had been negative.
LABORATORY FINDINGS
The hemoglobin level was 50 g/L (5.0 g/dL), with a
mean corpuscular volume of 66.7 fL (66.7 Mm3)* a mean
corpuscular hemoglobin concentration of 313 g/L (31.3
REPORT OF A CASE
g/dL), and an absolute reticulocyte count of 104 X 109/
L (104,000 mm -3 ). The white blood cell count was 6.9
In April 1989, a four-year-old Samoan girl was referred to the Pediatric
X 109/L (6,900 mm -3 ), with a normal differential analysis,
Hematology/Oncology Service at Tripler Army Medical Center for evaluation of recurrent anemia associated with significant hepatosplenoand the platelet count was 555 X 109/L (555,000 mm -3 ).
megaly. The child's medical history included chronic hypochromic, miAbnormal forms included teardrops, ovalocytes, and target cells. Serum electrolytes, liver enzymes, and renal
From the Departments of'Pathology and Pediatrics, Tripler Army function tests were normal. Iron studies showed a total
iron concentration of 3.40 //mol/L (19 Mg/dL) (normal,
Medical Center, Honolulu, Hawaii.
65-175 Mg/dL), TIBC of 12.36 ^mol/L (69 Mg/dL) (norReceived August 31,1990; accepted for publication October 23,1990.
mal,
250-410), and ferritin level of 783 jug/L (783 ng/
The conclusions and opinions expressed are those of the authors and
mL). Serologic results for hepatitis B virus, hepatitis A
do not necessarily reflect the position or policy of the Department of
Defense, the Department of the Army, the Army Medical Department,
virus, Toxoplasma, and cytomegalovirus were negative.
or the Health Services Command.
Serum protein electrophoresis showed a significantly deAddress reprint requests to Dr. Woods: Box 304, Tripler Army Medical
creased beta-globulin fraction, resulting from the absence
Center, Honolulu, Hawaii 96859-5000.
215
216
CLINICAL CHEMISTRY
Single Case Report
CONTROL SERUM
FIG. 1. Serum protein electrophoresis strip. Arrow marks normal location of the transferrin band, which is easily visualized in the control.
FIG. 2. Liver biopsy with marked hemosiderosis. Pearl's iron stain (X600).
A.J.C.P. • August 1991
HAMILL, WOODS, AND COOK
217
Congenital Atransferrinetnia
of the TRF band (Fig. 1). TRF was not detected by nephelometry. The mother's TRF level was 1.59 g/L (159 mg/
dL) (normal, 220-400 mg/dL).
A bone marrow aspirate was hypercellular, with a decreased myeloid-erythroid ratio. Iron stores were decreased. To assess the patient's hepatomegaly, a percutaneous liver biopsy was performed. There was a striking
amount of Prussian blue-positive golden brown pigment
(iron) in the hepatocytes and Kupffer cells (Fig. 2). Early
bridgingfibrosiswas focally present.
DISCUSSION
Transferrin (siderophilin) is a glycoprotein with a molecular weight of approximately 90,000 daltons and consists of a single polypeptide chain. It is synthesized primarily in the liver, but the reticuloendothelial system
(RES) and some endocrine glands also have the capacity
to produce TRF. In the plasma, TRF is bound not only
to iron, but also to copper, zinc, calcium, and cobalt. A
single TRF molecule binds two molecules of iron in association with an anion, which usually is bicarbonate.
Iron is derived from catabolized hemoglobin and intestinal
absorption. TRF then releases the iron for integration into
ferritin and hemosiderin in the RES and into cells that
synthesize iron-containing compounds (hemoglobin,
myoglobin, cytochromes).1
Transferrin can be assayed by nephelometry or radioimmunodiffusion and has a normal range of 2.0-4.0
g/L (200-400 mg/dL). Another crude measurement of
TRF is the TIBC, but it will overestimate the actual TRF
because other plasma proteins such as albumin also bind
iron.2
Because TRF is a negative acute-phase reactant, low levels
occur in many inflammatory and neoplastic conditions.
Other conditions, such as liver disease (decreased synthesis)
and nephropathies or enteropathies (increased loss), also can
lead to decreased serum levels. In some cases, the levels are
as low as those in CAT.3"5 However, the complete absence
or trace levels of TRF are exceedingly rare, with only seven
cases having been reported.4,6"10
In these examples (Table 1), the children had severe
microcytic, hypochromic anemia, with a low iron level
and a low TIBC but elevated ferritin levels. Serum TRF
levels ranged from undetectable to 0.39 g/L (39 mg/dL).9
No other associated congenital anomalies or syndromes
have been reported with this disorder. In addition to the
severe anemia, there are major findings related to iron
overload, which often is exacerbated by treatment with
iron or blood transfusions. Symptoms are associated with
increased iron deposition in the liver and RES. The patients of Heilmeyer and associates and Dorantes-Mesa
and associates and our patient all had severe hepatic hemosiderosis that was documented by liver biopsy or autopsy.4,7 The second of these patients also had splenic
involvement. However, treatment with iron or blood
transfusions probably increased the amount of iron deposition in these three cases.
The exact cause of CAT is not entirely clear, but, because parents of all of the affected children have low levels
of TRF, transmittance of an autosomal recessive trait is
suggested strongly. The putative carriers have no symptoms and are not anemic.7,8,10 Thorough evaluation of
additional cases of CAT or DNA analysis might help clarify this issue.
Purified human TRF, as used by Kawakami and associates, has been effective in the treatment of CAT.''
One patient had a dramatic increase in hemoglobin."
Unfortunately, preparation of TRF is difficult and expensive. Other treatment modalities include transfusion of
fresh-frozen plasma and the use of iron chelators. Our
patient was treated with the latter two modalities, with a
significant increase in hemoglobin concentration and increased urinary excretion of iron. Of course, erythrocyte
transfusions are contraindicated, because these increase
iron storage.
Data are limited on the prognosis of patients with CAT.
As stated previously, three of six patients had extensive
TABLE 1. HEMATOLOGIC AND IRON METABOLISM DATA ON CAT CASES
Transferrin g/L (mg/dL)
Author
Year
Age/Sex
Heilmeyer4
Cap6
Sakata9
Goya8
Walbaum10
Dorantes-Mesa7
Dorantes-Mesa7
Hamill (this study)
1961
1968
1969
1972
1971
1986
1986
1990
7/F
11 mos/F
10/F
8/M
7/F
9/F*
3/F*
4/F
Hemoglobin
g/L (gldL)
96
48
32
64
91
79
79
50
(9.6)
(4.8)
(3.2)
(6.4)
(9.1)
(7.9)
(7.9)
(5.0)
Iron iimol/L
frg/dL)
TIBC (nmoll
L (v-gldh)
1.61 (9)
5.37 (30)
2.87(16)
2.15(12)
2.51 (14)
3.40(19)
5.91
5.37
14.51
8.24
3.58
3.40(19)
12.56(69)
• Siblings.
Vol. 96 • No. 2
(33)
(30)
(81)
(46)
(20)
Patient
0.044 (4.4)
None
0.390 (39)
Trace
None
None
0.062 (6.2)
None
Parents M/F
0.800 (80)/1.060 (106)
Normal/Normal
1.100 (110)/1.150 (115)
1.59(159)/—
218
CLINICAL CHEMISTRY
Single Case Report
hemosiderosis of the liver, and one died. At the time of
the case report, one patient who received purified TRF
was alive after 17 years." Untreated patients probably
will die early from hemochromatosis or congestive heart
failure.
Acknowledgment. The authors thank Mineko Nagatoshi for her assistance in preparing this manuscript.
REFERENCES
1. Tietz NW. Fundamentals in clinical chemistry. 3rd ed. Philadelphia:
WB Saunders, 1987:333-334.
2. Bannerman RM. Genetic defects of iron transport. Fed Proc 1976;35:
2281-2285.
3. Gaston Morata JL, Rodriguez CA, Urbano JF, et al. Atransferrinemia
secondary to hepatic cirrhosis, hemochromatosis, and nephrotic
syndrome. Rev Esp Enferm Apar Dig 1982;62:491-495.
4. Heilmeyer VL, Keller W, Vivell O, et al. Congenital atransferrinemia
in a seven-year-old child. Dtsch Med Wochenschr 1961 ;86:17451751.
5. Oliva G, Dominici G, Latini P, Cozzolino G. Atransferrinemic nephrotic syndrome. Clinical contribution and etiopathogenetic
evaluation. Minerva Med 1968;59:1297-1309.
6. Cap J, Lebotska V, Mayerova A. Congenital atransferrinemia in an
eleven-month-old baby. Cesk Pediatr 1968;23:1020-1025.
7. Dorantes-Mesa S, Marquez JL, Valencia-Mayoral P. Iron overload
in hereditary atransferrinemia. Boletin Medico del Hospital Infantil de Mexico 1986;43:99-101.
8. Goya N, Miyazaki S, Kodate S, Ushio B. A family of congenital
atransferrinemia. Blood 1972;40:239-245.
9. Sakata T. A case of congenital atransferrinemia. Shonika Shinryo
1969;32:1522-1528.
10. Walbaum R. Congenital deficiency of transferrin. Lille Medical
1971;16:1122-1124.
11. Kawakami T, Sone Y, Numajiri S, Sakata T. Replacement therapy
for a patient with congenital atransferrinemia—therapeutic effect
of apotransferrin. Rinsho Ketsueki 1981;22:1708-1713.
A.J.C.P. • August 1991