On the Hyperferritinemia and Hereditary Cataract Syndrome

doi:10.4236/ojbd.2012.21002

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Open Journal of Blood Diseases, 2012, 2, 11-13

http://dx.doi.org/10.4236/ojbd.2012.21002 Published Online March 2012 (http://www.SciRP.org/journal/ojbd) 11

On the Hyperferritinemia and Hereditary Cataract

Syndrome

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: *[email protected]

Received December 11th, 2011; revised January 26th, 2012; accepted February 10th, 2012

ABSTRACT

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.

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

(A)

350

700

1050

1400

TS (%)

Ferritin (ng/mL)

(B)

100

Dec. May June JulyOct.

MCV (f L)

Hb (g/L)

(C)

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

figure).

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

syndrome.

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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