Open Journal of Blood Diseases, 2012, 2, 11-13 Published Online March 2012 ( 11
On the Hyperferritinemia and Hereditary Cataract
Maria José Pérez-Lucena1, María Sierra Moreno-Rosel2, María Sagarra-Tió2, Jo r di Félez2*
1Area Bàsica de Salut (ABS) Serraparera, Cerdanyola del Vallès, Barcelona, Spain; 2Area Bàsica de Salut (ABS) Canaletes, Institut
Català de la Salut (ICS), Cerdanyola del Vallès, Barcelona, Spain.
Email: *
Received December 11th, 2011; revised January 26th, 2012; accepted February 10th, 2012
Introduction: Mutations in the promoter region of ferritin light gene can induce an uncontro lled over expression of this
protein. Consequently, ferritin is found in seru m at very high levels (~1000 ng/mL) and it accumulates in the crystalline
lens, generating cataracts. This entity is known as hyperferritin and hereditary cataract syndrome (HHCS) which is in-
herited in an autosomal dominant manner. Case Presentation: We describe a family affected by HHCS. The proband
was identified among subjects submitted to a biological screening for hemochromatosis. He had very high levels of se-
rum ferritin (~900 ng/mL) with normal transferrin saturation (TS). The proband has a single H63D HFE-gene mutation
and normal HAMP-gene. He was submitted to periodical phlebotomies that induced anemia and a decrease in TS but no
changes on serum ferritin levels. Analyses of promoter region of ferritin-light chain gene showed a 39C > T mutation,
responsible for HHCS. The proband’s sister carried also this mutation. Both subjects had developed cataracts. Discus-
sion: Similar to the first family described carrying this syndrome and to other cases reported, the proband was errone-
ously submitted to phlebotomies. Clinical consequences are illustrated in this report. HHCS is an infrequent entity
which has to be correctly identified. The unique therap eutic approach to this syndrome must be cataract surg ery.
Keywords: Hyperferritinemia; Iron Overload; Cataract; Hyperferritinemia and Hereditary Cataract Syndrome (HHCS)
1. Introduction
Prevalence of congenital cataract is estimated in 2.2 - 2.4
over 10,000 births [1]. Approximately 30% of patients
suffering cataract have familiar history and frequently
they are transmitted in an autosomal dominant manner
[1]. The hyperferritinemia and hereditary cataract syn-
drome (HHCS) has a relevant role among these syn-
dromes. HHCS was first described in 1995 and it is
characterized by an early onset of cataracts and the de-
tection of very high serum ferritin levels [2-4]. It has an
ubicous geographic distribution, affecting individuals
from Europe, America, Australia and India [5]. This
syndrome has a unique clinical complication: the pre-
sence of cataracts with distinct morphology and variable
period of onset which depends on both the molecular
type of HHCS and on the ethnicity of affected individu-
als [2-4]. HHCS patients have high serum ferritin levels
but without iron-overload (reviewed in [6]). The associa-
tion of cataract with hyperferritinemia and the fact that
measurement of serum ferritin levels is broadly used in
routine blood tests, confers an emergent relevance to
HHCS which should be id entif ied by primary care practi-
tioners, ophthalmologists, pediatricians, gastroenterolo-
gists and hematologists. We hereby describe a patient
affected by HHCS that was detected during a multicenter
primary care case-finding study on hereditary hemo-
chromatosis carried out by our group among 2739 indi-
viduals [7].
2. Case Report
A 24 year-old male was enrolled in a biological study for
screening of hemochromatosis. In a first blood test, he-
moglobin of 15.8 g/L and serum ferritin levels of 900
ng/mL were detected as unique abnormalities. Transfer-
rin saturation (TS) was normal. Hyperferritinemia was
confirmed in two additional measurements. The proband
has a single H63D HFE-gene mutation and normal
HAMP-gene. Panel A of Figure 1 depicts iron-related
abnormalities found in his family. Due to elevated serum
ferritin levels found, the patient was sub mitted to six 400
mL phlebotomy that induced anemia and a decrease in
TS but without changes on serum ferritin levels (Panels
B and C). Medical history was reassessed and then, a
cataract surgery was identified at early childhood. Analy-
sis of ferritin light chain (FtL) promoter showed a 39C >
*Corresponding a uthor.
Copyright © 2012 SciRes. OJBD
On the Hyperferritinemia and Hereditary Cataract Syndrome
a) 24
b) 29
c) 943
d) 39C>T
a) 21
b) 22
c) 1117
d) 39C>T
a) 48
b) 35
c) 1200
d) ND
TS (%)
Ferritin (ng/mL)
Dec. May June JulyOct.
MCV (f L)
Hb (g/L)
Figure 1. Family affected by Hyperferritinemia and He-
reditary Cataract Syndorme (HHCS). Panel A: Circles,
women. Square, men. Affected members filled in black.
Propositus indicated by arrow. a) (in small letter) age; b) (in
small letter) Transferrin Saturation (%); c) (in small letter)
serum ferritin levels (ng/mL); d) (in small letter) Type of
mutation in the promoter region of light chain ferritin gene;
ND) Not determined. There are no data on the propositus’s
father. Panel B: Changes in serum ferritin levels (circles)
and transferrin saturation (TS, triangles) induced by phle-
botomy (since month of May). There is a fast decrease in TS
without marked changes in serum ferritin levels that re-
main ~ 900 ng/mL. Panel C: Hemoglobin (g/mL, diamonds)
and MCV (fL, squares) changes induced by phlebotomy
(for details, see the text).
T mutation, responsible for HHCS. This mutation was
also indentified in the proband’s sister (21 year-old) and
not determined in mother’s proband (48 year-old). Both
were also submitted to crystalline surgery at early child-
hood and had normal transferrin saturation measurements
but very high ferritin levels (>1000 ng /mL, see details in
3. Discussion
Ferritin is a multi polymer formed by two molecules of
different molecular weight. Whereas heavy chain ferritin
gene is regulated at a transcriptional level by several on-
cogenes, cytokines, etc., FtL gene is mainly modulated
by iron at a translation level by a number of Iron Regu-
latory Proteins (IRP’s 1 - 2) [8]. Abnormal up-regulation
of FtL gene may be due to up to 31 distinct base muta-
tions of these regions which induce very high serum fer-
ritin levels [9,10]. In these cases, ferritin accumulates in
lymphocytes, without clinical consequences and in crys-
talline lens developing cataracts [5]. The high ferritin
levels is consequence of the increased synthesis of the
FtL chain but not of total body iron, since the light chain
ferritin does not participate in iron oxidation and storage
(reviewed in 6). Mutations in FtL are extremely rare and
associated to either HHCS or to a novel genetic dominant
unexplained hyperferritinemia that has been recently
described in a large family (n = 22) [11]. In these sub-
jects, mutations in IRE sequence of FtL promoter were
not identified but the authors found a single mutation
(p.Thr30Ile) in the coding sequence FtL in half the fa-
milial and in few isolated cases but not in more than 500
normal controls. This new unexplained hyperferritinemia
is not associated to relevant clinical data.
We have reported a new Spanish family affected by
HHCS due to a 39C > T substitution within the IRE re-
gion of FtL promoter. The proband of this family carried
also a single H63D mutation of HFE gene, fact also
found in other recently described families in Spain [12].
In HHCS, hyperferritinemia is not paralleled with a
proper iron-overload and thus no pathologies associated
to iron excess are developed. Thus, no interventions such
as phlebotomy are needed in these patients. However,
some affected subjects, such as the one described in this
letter and others previously reported [2,6,9], have been
treated or submitted to biopsy to assess liver iron-over-
load. Sometimes, these patients are also stigmatized as
carriers of an iron-overload syndrome. These practices
are due to the unfamiliarity of the HHCS. Thus, we think
it is important to give diffusion to new cases of HHCS
and to reinforce a correct therapeutic approach of this
4. Acknowledgements
We thank Dr. Laura Cremonesi, Unit of Genomics for
the Diagnosis of Human Pathologies; DIBIT2; San Raf-
faele Scientific Institute: Milan, Italia, for molecular char-
acterization of the HHCS described. This work was sup-
ported by FIS 03/0459 an d FIS 08/0956.
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