Hyperferritinemia Cataract Syndrome Research Articles

Hereditary hyperferritinemia cataract syndrome with iron deficiency : a case report

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare disease characterized by high serum ferritin levels, congenital bilateral cataracts, and the absence of tissue iron overload. HHCS is a rare disease characterized by high serum ferritin levels, congenital bilateral cataracts, and the absence of tissue iron overload. In this case report, we aimed to present a young female patient with a history of cataracts in herself and her family members. Our patient had the dilemma of iron deficiency anemia and hyperferritinemia. As in our patient, patients with HHCS apply to many outpatient clinics and have difficulty in diagnosis. For this reason, we prepared our case to raise awareness.

Hyperferritinemia and non-HFE hemochromatosis: differential diagnosis and workup.

Hyperferritinemia is a common reason for referral to a hepatogastroenterologist. The most frequent causes are not associated with iron overload (e.g. inflammatory diseases, alcohol abuse, metabolic syndrome, etc.). However, hyperferritinemia can also be caused by a genetic variant in one of the iron regulatory genes, called hereditary hemochromatosis, often but not always associated with iron overload. A variation in the human Hemostatic Iron Regulator protein (HFE) gene is the most common genotype, but many other variants have been described. In this paper we discuss two cases of rare hyperferritinemia associated disorders, ferroportin disease and hyperferritinemia-cataract syndrome. We also propose an algorithm for evaluating hyperferritinemia, facilitating a correct diagnosis and preventing potentially unnecessary examinations and therapeutic actions.

Precision Medicine through Next-Generation Sequencing in Inherited Eye Diseases in a Korean Cohort.

In this study, we investigated medically or surgically actionable genes in inherited eye disease, based on clinical phenotype and genomic data. This retrospective consecutive case series included 149 patients with inherited eye diseases, seen by a single pediatric ophthalmologist, who underwent genetic testing between 1 March 2017 and 28 February 2018. Variants were detected using a target enrichment panel of 429 genes and known deep intronic variants associated with inherited eye disease. Among 149 patients, 38 (25.5%) had a family history, and this cohort includes heterogeneous phenotype including anterior segment dysgenesis, congenital cataract, infantile nystagmus syndrome, optic atrophy, and retinal dystrophy. Overall, 90 patients (60.4%) received a definite molecular diagnosis. Overall, NGS-guided precision care was provided to 8 patients (5.4%). The precision care included cryotherapy to prevent retinal detachment in COL2A1 Stickler syndrome, osteoporosis management in patients with LRP5-associated familial exudative vitreoretinopathy, and avoidance of unnecessary phlebotomy in hyperferritinemia-cataract syndrome. A revision of the initial clinical diagnosis was made in 22 patients (14.8%). Unexpected multi-gene deletions and dual diagnosis were noted in 4 patients (2.7%). We found that precision medical or surgical managements were provided for 8 of 149 patients (5.4%), and multiple locus variants were found in 2.7% of cases. These findings are important because individualized management of inherited eye diseases can be achieved through genetic testing.

Cataract secondary to iatrogenic iron overload in a severely anemic patient

High levels of iron may be toxic and cause various pathologies in the human body, including the eye. Studies have shown increased iron concentration in certain subtypes of senile cataracts. High serum levels of its non-reactive depot form, ferritin, has also been associated with juvenile cataracts in hereditary hyperferritinemia-cataract syndrome. Whereas this form of hyperferritinemia is inherited, there is no report on cataract formation in iatrogenic hyperferritinemia. Herein, we report a 43-year-old case who was diagnosed with bilateral cataracts a few years after she received intensive intravenous iron replacement therapy for severe iron deficiency anemia.

Hereditary hyperferritinemia-cataract syndrome in three Czech families: molecular genetic testing and clinical implications

Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant disorder manifesting with high serum ferritin levels and the formation of early-onset cataracts, with numerous small opacities, predominantly in the lens cortex. HHCS is caused by mutations in the iron-responsive element of the FTL gene. The aim of this study was to establish a molecular diagnosis in three Czech probands with suspected HHCS. A complex ocular and systemic evaluation, including ferritin and iron measurements, was performed. The 5' untranslated region of FTL was directly sequenced in all available family members, followed by paternity testing in one family. Three different FLT pathogenic variants (c.-161C>T, c.-167C>T, and c.-168G>C) present in the heterozygous state were detected in each of the 3 probands. Two segregated with the disease phenotype within the families, but c.-167C>T occurred de novo (confirmed by paternity testing). Prior to establishing molecular diagnosis, two probands were misdiagnosed with hemochromatosis. One individual, aged 43years, underwent phlebotomy; another, aged 8.5years, was treated with the iron chelator deferasirox, leading to life-threatening acute hyperammonemia, without severe liver injury. Lack of family history does not exclude HHCS, because the pathogenic variant can arise de novo. Noncoding regions are often omitted from diagnostic gene panels, thus evading detection. Careful clinical evaluations and targeted genetic screening are important for avoiding potentially harmful treatments.

Hereditary hyperferritinaemia-cataract syndrome (HHCS) - an underestimated condition: ferritin light chain variant spectrum in German families.

Background In hereditary hyperferritinaemia-cataract syndrome (HHCS), single nucleic acid alterations in the ferritin light chain (L-ferritin) iron response element (IRE) constitutively derepress ferritin synthesis, resulting in hyperferritinaemia, L-ferritin deposits in the lens of the eye and early bilateral cataract onset. Methods In this study, six German families with putative HHCS were analysed. Clinical diagnosis of HHCS was based on medical history, evaluation of ferritin serum levels, transferrin saturation and clinical ophthalmological examination. Diagnosis was confirmed by polymerase chain reaction (PCR)-based DNA sequencing of the L-ferritin IRE. Results Genetic analysis of the L-ferritin IRE revealed relevant single nucleic acid alterations in each of the affected families. Variants c.-168G > A, c.-168G > U and c.-167C > U were located in the C-bulge region; and variants c.-161C > U and c.-157G > A were located in the hexanucleotide loop of the L-ferritin IRE. Conclusions Family history of hyperferritinaemia and juvenile cataracts are strong indicators of HHCS. Genetic analysis of the L-ferritin IRE is a straightforward procedure to confirm the diagnosis. Accurate diagnosis of hyperferritinaemia can avoid unnecessary treatment by venesection, and focus attention on early cataract detection in offspring at risk.

Frequent Mutation in the FTL Gene Causing Hyperferritinemia Cataract Syndrome in Turkish Population Is c.-160A>G

Objective:Hyperferritinemia cataract syndrome (HFCS) is an autosomal dominantly inherited disease characterized by increased serum ferritin levels and bilateral cataract formation in the early period of life. Heterozygote mutations in the 5’ untranslated region of the L-ferritin gene (FTL) have been reported to cause this disease. In this study, our purpose was to research the FTL gene mutations that cause HFCS in Central Anatolia and the clinical effects of these mutations.Materials and Methods:Seventeen patients from 6 families with high ferritin levels in performed serum measurements, those who were found to have cataracts in eye examinations, and families with vertical inheritance, since the disease is autosomal dominant, were included in the study. Exons, exon-intron boundaries, and 5’ and 3’ untranslated regions of FTL (NM_000146) were sequenced using the Sanger sequencing method.Results:The female/male ratio of the patients was 7/10. All of the patients were found to have c.-160A>G heterozygous mutation in the FTL gene.Conclusion:In the Turkish population, the prevalence of HFCS is about 1/100,000 and the commonly observed mutation is c.-160A>G mutation.

Frequent Mutation in the FTL Gene Causing Hyperferritinemia Cataract Syndrome in Turkish Population is c.-160 A>G

Frequent Mutation in the FTL Gene Causing Hyperferritinemia Cataract Syndrome in Turkish Population is c.-160 A>G

Hereditary Hyperferritinaemia-Cataract Syndrome Classical presentation for differential diagnosis

Hereditary Hyperferritinaemia-Cataract Syndrome Classical presentation for differential diagnosis

Functional characterization of a novel non-coding mutation \u201cGhent +49A\u2009>\u2009G\u201d in the iron-responsive element of L-ferritin causing hereditary hyperferritinaemia-cataract syndrome

Hereditary hyperferritinaemia-cataract syndrome (HHCS) is a rare disorder usually caused by heterozygous mutations in the iron-responsive element (IRE) in the 5′ untranslated region (5′UTR) of the L-ferritin gene (FTL), disturbing the binding of iron regulatory proteins (IRPs) and the post-transcriptional regulation of ferritin expression. Here, the proband of a consanguineous family displayed moderate bilateral cataracts and elevated serum ferritin in the absence of iron overload. The parents and siblings showed variable degrees of mild bilateral cataracts combined with elevated levels of circulating ferritin. Sequencing of FTL identified a novel 5′UTR mutation c.-151A > G, also named “Ghent +49A > G”. The zygosity of the mutation, occurring in homozygous and heterozygous state in the proband and other affected family members respectively, correlated well with severity of ophthalmological and hematological manifestations. The substitution is expected to impair the secondary structure of the upper IRE stem. Functional characterization of +49A > G by electrophoretic mobility shift assays demonstrated a reduced binding affinity for IRP1 compared to the wild-type IRE of FTL. Overall, we have expanded the repertoire of deleterious biallelic FTL IRE mutations in HHCS with this novel +49A > G mutation, the zygosity of which correlated well with the disease expression.

A novel double nucleotide variant in the ferritin‐L iron‐responsive element in a Finnish patient with hereditary hyperferritinaemia‐cataract syndrome

To present a novel Finnish double nucleotide variant in the iron-responsive element (IRE) of the ferritin L-chain gene (FTL) leading to hyperferritinaemia-cataract syndrome (HHCS). Genomic DNA extracted from peripheral blood leucocytes and synthetized with three different primers flanking the IRE in the FTL 5'-untranslated region of the FTL was used in polymerase chain reaction (PCR). Thereafter, Sanger sequencing was performed on the 487-bp and 602-bp PCR amplification products with specific primers to reveal FTL IRE mutations. A 58-year-old female patient with elevated serum ferritin level (1339μg/l) was diagnosed with HHCS after extensive workup. Genetic testing identified a novel double point mutation g.48965355G>C (chr19, hg19) and g.48965356G>T (chr19, hg19) in the lower stem region of the IRE canonical structure of the FTL. After excluding other causes, elevated serum ferritin level in a person with early onset cataract is indicative for HHCS, a genetic disorder caused by mutation in the IRE of the FTL.

FTL +32G>C Mutation in Hereditary Hyperferritinemia Cataract Syndrome: a New Italian Family

Background: We described a new Italian family with seven members affected by hereditary hyperferritinaemia cataract syndrome (HHCS). It is a rare autosomal dominant disease caused by mutations of the iron-responsive element (IRE) of the ferritin light chain gene (FTL). These mutations inhibit the interaction between IRE and the iron responsive protein (IRP), with concomitant upregulation of FTL synthesis. Methods: The family diagnoses of HHCS took place after finding high ferritin levels in a six-year-old girl. The family history revealed the presence of early-onset cataracts and hyperferritinaemia (1129 ng/mL) in her 34 year old mother, were performed, for all subjects, clinical, haematological, biochemical and genetic analysis. Ophthalmological examinations were performed at the time of diagnosis and again after three years for follow up. Results: Seven members of the family had bilateral and symmetrical cataracts, normal iron and haematological parameters except for high serum ferritin levels. Genetic testing confirmed the diagnosis of HHCS, demonstrating the presence of a heterozygous point mutation at position +32 (c.-168G>C) in the FTL gene. Conclusion: The ophthalmological follow-up showed slowly progressive cataracts mainly involving the nucleus, with characteristics of lens opacity and visual acuity data underlining a benign feature of syndrome. This case shows how important the family history is in reaching a correct diagnosis and avoiding unnecessary and invasive analysis, such as liver biopsy, the consequences of unwarranted treatment such as chelation therapy and adverse effects of phlebotomy. HHCS should be considered in the differential diagnosis of childhood hyperferritinaemia, especially in the presence of normal transferrin saturation.

Hereditary Hyperferritinemia-cataract Syndrome

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder associated with high plasma ferritin concentration without iron overload and early-onset bilateral cataract. The deregulation of ferritin production in HHCS is caused by mutations in the iron-responsive elements (IREs) of the ferritin L-subunit gene (FTLgene) – interfering with the high-affinity interaction between IREs and iron regulatory proteins (IRPs), disturbing the negative regulatory control of ferritin synthesis and resulting in excessive production of L-ferritin. We report a 44-year-old woman initially suspected of having hereditary haemochromatosis and later together with family members diagnosed with HHCS. Genetic analysis showed heterozygosity for a G32T point mutation (Paris 2 mutation) in the IRE located in the 5' untranslated region (UTR) of theFTLgene. The differential diagnosis of hereditary haemochromatosis and HHCS together with the rarity and the versatile phenotype in HHCS obscures the diagnostic process, which emphasises the importance of the correct diagnosis of HHCS in order to prevent unnecessary phlebotomy.

Hereditary Hyperferritinemia Cataract Syndrome as a Cause of Childhood Hyperferritinemia

A 2-year-old female was presented with high levels of serum ferritin (890 ng/mL) in a routine blood test. Clinical and laboratory investigations excluded the presence of iron overload and secondary causes of hyperferritinemia. A detailed family history and laboratory examinations revealed the presence of early-onset cataract in her 33-year-old mother, who also displayed hyperferritinemia (633 ng/mL), similar to other family members. Genetic testing confirmed the diagnosis of hereditary hyperferritinemia cataract syndrome (HHCS), demonstrating a C39>G (c.-161C>G) mutation into FTL gene. HHCS should be considered in the differential diagnosis of childhood hyperferritinemia, especially in the presence of normal transferrin saturation.

Raised serum ferritin concentration in hereditary hyperferritinemia cataract syndrome is not a marker for iron overload

Hyperferritinemia and bilateral cataracts are features of the rare hereditary hyperferritinemia cataract syndrome (HHCS; OMIM #600886). HHCS is an autosomal dominant condition caused by mutations which increase expression of the ferritin light polypeptide (FTL) gene. We report a patient with HHCS who was misdiagnosed and treated as having hemochromatosis, in whom a heterozygous c.-160A>G mutation was identified in the iron responsive element (IRE) of FTL, causing ferritin synthesis in the absence of iron overload. This report demonstrates the need for clinical awareness of HHCS as a cause of hyperferritinemia in the absence of iron overload and provides a possible diagnostic schema. (Hepatology 2014;59:1204–1206)

Novel mutations in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome

BackgroundHereditary Hyperferritinaemia Cataract Syndrome (HHCS) is a rare autosomal dominant disease characterized by increased serum ferritin levels and early onset of bilateral cataract. The disease is caused by mutations in the Iron-Responsive Element (IRE) located in the 5′ untranslated region of L-Ferritin (FTL) mRNA, which post-transcriptionally regulates ferritin expression.MethodsWe describe two families presenting high serum ferritin levels and juvenile cataract with novel mutations in the L-ferritin IRE. The mutations were further characterized by in vitro functional studies.ResultsWe have identified two novel mutations in the IRE of L-Ferritin causing HHCS: the Badalona +36C > U and the Heidelberg +52 G > C mutation. Both mutations conferred reduced binding affinity on recombinant Iron Regulatory Proteins (IPRs) in EMSA experiments. Interestingly, the Badalona +36C > U mutation was found not only in heterozygosity, as expected for an autosomal dominant disease, but also in the homozygous state in some affected subjects. Additionally we report an update of all mutations identified so far to cause HHCS.ConclusionsThe Badalona +36C > U and Heidelberg +52 G > C mutations within the L-ferritin IRE only mildly alter the binding capacity of the Iron Regulatory Proteins but are still causative for the disease.

Homozygous mutation of the 5'UTR region of the L-Ferritin gene in the hereditary hyperferritinemia cataract syndrome and its impact on the phenotype

Hereditary hyperferritinemia cataract syndrome (HHCS) is an autosomal dominant disorder characterized by hyperferritinemia without iron overload and early-onset bilateral cataract induced by L-ferritin accumulation in the lens.[1][1] Affected patients harbor heterozygous mutations within the iron

The Hereditary Hyperferritinemia-Cataract Syndrome in 2 Italian Families

Two 8- and 9-year-old brothers were referred to the Pediatric Oncology Unit, Perugia General Hospital, because of hyperferritinemia. Both had a history of bilateral cataract and epilepsy. Genetic investigation revealed two distinct mutations in iron haemostasis genes; homozygosity for the HFE gene H63D mutation in the younger and heterozygosity in the elder. Both displayed heterozygosity for C33T mutation in the ferritin light chain iron response element. A 7-year-old boy from another family was referred to our unit because of hyperferritinemia. Genetic analyses did not reveal HFE gene mutations. Family history showed that his mother was also affected by hyperferritinemia without HFE gene mutations. Magnetic resonance imaging in the mother was positive for iron overload in the spleen. Cataract was diagnosed in mother and child. Further genetic investigation revealed the C29G mutation of the ferritin light chain iron response element. C33T and C29G mutations in the ferritin light chain iron response element underlie the Hereditary Hyperferritinemia-Cataract Syndrome (HHCS). The HFE gene H63D mutation underlies Hereditary Haemochromatosis (HH), which needs treatment to prevent organ damages by iron overload. HHCS was definitively diagnosed in all three children. HHCS is an autosomal dominant disease characterized by increased L-ferritin production. L-Ferritin aggregates accumulate preferentially in the lens, provoking bilateral cataract since childhood, as unique known organ damage. Epilepsy in one case and the spleen iron overload in another could suggest the misleading diagnosis of HH. Consequently, the differential diagnosis between alterations of iron storage system was essential, particularly in children, and required further genetic investigation.

A Study of the Hereditary Hyperferritinemia Cataract Syndrome in Patients of Greek Origin

Abstract 3205 Background:Hereditary hyperferritinemia cataract syndrome (HHCS) is an autosomal dominant disorder characterized by elevated serum L-ferritin and early onset bilateral cataracts. The syndrome, first described in Italy and France in 1995, is caused by mutations in the iron responsive element (IRE) of the L-ferritin gene (FTL-ferritin light chain) on chromosome 19q13.3. The conformational changes in the mutated IRE disrupt the binding of the iron regulatory proteins (IRPs) to the IRE, resulting in loss of the posttranscriptional control in L-ferritin synthesis. L-ferritin is constitutively expressed in tissues, irrespective of cellular iron status and without otherwise disrupting cellular iron metabolism. Despite the five to twenty-fold increase in serum L-ferritin, there is no clinical or laboratory evidence of iron overload. Serum iron and transferrin saturation remain within normal limits. Visual impairment and early cataract formation is the only clinical symptom of HHCS, with lens replacement being the only treatment needed. Extensive and invasive investigations in the undiagnosed hyperfferitinemic patient, as well as unnecessary treatment with phlebotomies, can be avoided with awareness of the syndrome, leading to the correct clinical and molecular diagnosis. Aim:HHCS has been previously reported in a limited number of patients of Greek origin, with the study of three unrelated families in Greece. Papanikolaou et al. (Blood Cells Mol Dis. 2006) detected the C39>G mutation in the IRE of the FTL in all affected individuals. Our aim was to further investigate the syndrome within the Greek population, both phenotypically and genetically. Methods:We investigated 81 patients with undiagnosed hyperferritinemia referred to the Hepatology Outpatients Clinic of the 1st Department of Internal Medicine at “Laikon” General Hospital in Athens. For all patients full medical history and clinical examination (including ophthalmological evaluation) was performed, and laboratory investigations were tailored accordingly. Where indicated from the medical history and laboratory findings, molecular analysis for mutations in the IRE of the FTL was performed using direct DNA sequencing. Results:From the total of 81 patients referred for undiagnosed hyperferritinemia, 18 unrelated subjects had a positive history of cataract and elevated ferritin. In those subjects ferritin levels ranged from 600 to 2070μg/L (normal values: 12–160μg/L). Serum iron was within normal limits and transferrin saturation ranged from 9 to 40%. Cataract diagnosis was reported as early as 5 years of age and 8 out of the 18 subjects had undergone surgery for lens replacement at the time of referral. From the 18 subjects that were screened for mutations in the IRE of the FTL, mutations were detected in 12 unrelated subjects. Ten out of the 12 individuals were positive for the previously described C39>G point mutation. The other two subjects were found to carry the A40>G mutation. The A40>G mutation has been described in the literature as part of the spectrum of mutations causing HHCS (Beaumont et al, Nat. Genet. 1995), however it has not up to now been reported in subjects of Greek origin. From the 12 subjects positive for either mutation, 8 reported positive family history for either early onset cataracts, hyperferritinemia or both. Where possible, clinical, laboratory and molecular investigations were extended to other members of these families. A total of 40 subjects from the members of the studied families fulfilled the clinical criteria of HHCS. Genetic testing was performed in 12 of them, revealing 11 subjects heterozygous for the C39>G mutation and 1 heterozygous for the A40>G mutation. Conclusion:HHCS is a non-iron loading, rare disorder that should be considered in all patients with unexplained hyperferritinemia, in order to avoid unnecessary investigations, potentially hazardous treatment and confer reassurance to the patient. Our findings contribute to the clinical and molecular characterization of the syndrome and extend the study of the disorder in the Greek population. Disclosures:No relevant conflicts of interest to declare.

Hereditary hyperferritinemia cataract syndrome in four patients with mutations in the IRE of the FTL gene

Hereditary hyperferritinemia cataract syndrome in four patients with mutations in the <scp>IRE</scp> of the <i><scp>FTL</scp></i> gene