Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hereditary Hyperferritinemia with Congenital Cataracts. Core disease mecha...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 16
• Snippets retrieved: 20

Relevant Papers

[1] Hereditary Hyperferritinemia-Cataract Syndrome: A Pediatric Case Without Congenital Cataract

• Authors: Anusha Hemanna, Richard Sidlow
• Year: 2025
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/845f6f162d4735c88a7a50326b0fe232ae6b2ad3
• DOI: 10.7759/cureus.95062
• PMID: 41281144
• PMCID: 12635498
• Summary: A three-year-old male patient with incidentally detected hyperferritinemia who was found to harbor the c.-168G>T mutation in the FTL gene is reported, confirming hereditary hyperferritinemia-cataract syndrome (HHCS).
• Evidence snippets:
• Snippet 1 (score: 0.616) > Congenital, pediatric or early-onset cataracts, or unexplained hyperferritinemia in the absence of iron overload, either in isolation or in combination in an individual or a family, should raise clinical suspicion of HHCS. The diagnosis of HHCS was made after three generations of the patient's family showed an autosomal dominant inheritance pattern of hyperferritinemia with a history of cataracts. Hence, early identification of uncommon hereditary disorders is made possible by family history, which is a crucial screening tool for interpreting abnormal clinical findings. Our case, with its four-generation transmission primarily affecting males, raises the possibility of additional biological mechanisms, such as imprinting effects or sex-linked genetic/environmental modifiers, which merit further study. This case not only supports the importance of early diagnosis of HHCS but also suggests the need for further studies to elucidate the mechanisms of phenotypic variability, such as the age of cataract onset and the potential role of modifying factors. Further elucidation of these factors may lead to improvements in patient care and guide targeted therapy in the future. Prompt referral to a geneticist for directed testing of both the exonic and 5'-intronic space covering the FTL gene should follow the detection of these clinical findings and/or family history. Further research into the role of known variants causing this disease and clarification of genotype/phenotype correlations could reveal further insights into the iron regulation system, which is warranted.
• Snippet 2 (score: 0.531) > The uncommon condition known as hereditary hyperferritinemia-cataract syndrome (HHCS) is typified by elevated serum ferritin levels, congenital bilateral cataracts, and no tissue iron overload [1,2]. Otherwise known as Bonneau-Beaumont Syndrome, this syndrome was initially identified as an autosomal dominant hereditary disease in 1995 by two separate research teams in France and Italy [3]. An important feature of HHCS is the progressive cataracts with highly distinctive morphology [4]. Approximately one in 200,000 people has the condition. However, this figure is likely understated since, even in cases where iron overload is not present, the illness is sometimes misdiagnosed as hereditary hemochromatosis because of hyperferritinemia. > The iron-responsive element (IRE) found upstream of the light ferritin gene (FTL) is mutated in HHCS. The gene product of a classical IRE is an mRNA structure that post-transcriptionally controls the production of proteins involved in iron metabolism by interacting with the iron regulatory proteins (IRP1 and IRP2). The FTL gene itself has been shown to contain at least 47 mutations that cause HHCS, including 36 singlenucleotide mutations, nine deletions, and two insertion-deletions [5]. Families with HHCS have been found to have at least 25 distinct genetic changes, including those affecting the complete IRE structure. There have also been reports of isolated instances brought on by de novo mutations [6]. While some of these genetic changes impact the stems or the bulge of the IRE structure and change its conformation, others disrupt the loop that directly interacts with iron regulatory proteins, which result in the uncontrolled synthesis of ferritin and inhibit iron binding [7,8]. > While cataracts are the cardinal and well-documented ocular manifestation of HHCS, the correlation between genotype and the variability of the ocular phenotype, including factors such as age of onset and severity of cataracts, remains poorly understood [4]. Broader awareness and early diagnosis of this entity when hyperferritinemia is detected have the potential to improve visual outcomes for patients.
• Snippet 3 (score: 0.507) > Unlike Neofytou et al. (Table 2), who reported a sporadic case, our study identified a significant family history spanning four generations with congenital cataracts predominantly affecting males [9]. Furthermore, our genetic analysis revealed a heterozygous carrier status for the H63D variant of the HFE gene, contrasting with Alvarenga et al. (Table 2), who ruled out HFE gene mutations [10]. Notably, our study also found hyperferritinemia in first-degree relatives, differing from Morais et al. (Table 2), who reported normal ferritin levels in family members [11]. These differences highlight the complexity and variability of this condition. Serra et al. reported on a pediatric case of HHCS that did not present with cataracts; this case, unlike our case, involved exclusively maternal relatives of the male proband harboring a different variant (A37C) in FTL (Table 2) [12]. Our case involves four generations of exclusively male individuals, many of whom presented with congenital cataracts. Most other cases in the medical literature do not display such extreme gender specific segregation, which argues against an imprinting effect or segregation patterns being affected by the presence of specific exonic versus intronic variants driving the phenotype. However, given the paucity of cases reported to date, the preceding cannot be definitively ruled out. Additionally, there does not seem to be a correlation between the presence of a specific exonic versus intronic variant to explain the presence of congenital versus later onset of cataracts. However, genotype/phenotype correlation may be achievable based on measurement of time course of elevated ferritin levels as they relate to the specific variants known to cause HHCS to see if absolute levels or initiation/length of exposure to high ferritin levels may explain such this difference in phenotype (cataract formation in this syndrome being due to 10x elevation of ferritin levels within the lens). > Since hyperferritinemia is a biochemical indicator shared by both hereditary hemochromatosis and HHCS, the two conditions are misdiagnosed.

[2] Clinical and Molecular Clues to Diagnosing Hereditary Hyperferritinemia-Cataract Syndrome: Case Report and Literature Review

• Authors: Barbora Ludíková, L. Sochorcova, D. Jakšić, K. Hlusickova Kapralova, M. Horvathova
• Year: 2025
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/b0919b844c289eca02277e771ba54b57c67730ff
• DOI: 10.3390/genes16111381
• PMID: 41300832
• PMCID: 12652614
• Citations: 1
• Summary: A 12-year-old Czech girl with markedly elevated serum ferritin identified incidentally during workup for abdominal pain is evaluated, highlighting the translational relevance of combining molecular diagnostics, clinical evaluation, and family screening to improve recognition and management of HHCS and to prevent misdiagnosis and unnecessary iron-depletion therapy.
• Evidence snippets:
• Snippet 1 (score: 0.606) > Background: Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder characterized by persistently elevated serum ferritin and early-onset bilateral cataracts in the absence of systemic iron overload. It is caused by pathogenic variants in the iron-responsive element (IRE) of the FTL gene, leading to dysregulated L-ferritin synthesis. Methods: We evaluated a 12-year-old Czech girl with markedly elevated serum ferritin identified incidentally during workup for abdominal pain. Clinical assessment included biochemical, radiological, ophthalmological, and genetic testing of the proband and available family members. Results: Magnetic resonance imaging excluded systemic iron overload, while ophthalmological evaluation revealed bilateral cataracts. Family history indicated multiple affected relatives across three generations. Genetic testing confirmed a heterozygous FTL c.-168G>C variant. Additional screening for common HFE variants revealed heterozygous H63D in several family members, with no impact on ferritin or hepcidin levels. Beyond this case, we provide a comprehensive review of HHCS, including molecular mechanisms, an updated overview of reported FTL mutations, and ophthalmological features that distinguish HHCS cataracts from other congenital cataracts. Conclusions: This report underscores the translational relevance of combining molecular diagnostics, clinical evaluation, and family screening to improve recognition and management of HHCS, and to prevent misdiagnosis and unnecessary iron-depletion therapy.
• Snippet 2 (score: 0.532) > Hereditary hyperferritinemia-cataract syndrome (HHCS, OMIM #600886) is a rare autosomal dominant disorder characterized by persistently elevated serum ferritin and early-onset bilateral cataracts without systemic iron overload. The condition is caused by pathogenic variants in the iron-responsive element (IRE) within the 5 ′ untranslated region (UTR) of the ferritin light chain (FTL) gene located on chromosome 19, which encodes the light (L)-ferritin subunit [1][2][3]. Under physiological conditions, the IRE forms a stem-loop structure that binds iron regulatory proteins (IRPs), thereby inhibiting translation of FTL mRNA when cellular iron levels are low [4]. In HHCS, pathogenic variants disrupt this regulatory mechanism, leading to constitutive overproduction of L-ferritin. > Clinically, aside from isolated hyperferritinemia, the hallmark manifestation is progressive, bilateral cataract formation, usually developing in childhood or adolescence and often requiring surgical intervention [5]. This results from excessive accumulation of L-ferritin in the lens, with characteristic crystalline deposits that scatter light and impair vision. The severity of cataracts and serum ferritin levels may correlate with the specific IRE mutation [2]. The estimated prevalence of HHCS is around 1 in 200,000 individuals, though this is likely underestimated due to underdiagnosis, especially in milder or subclinical cases [1]. Fewer than 200 families have been reported worldwide, often identified incidentally during evaluation of unexplained hyperferritinemia [6,7]. Diagnosis relies on the detection of persistently elevated serum ferritin with otherwise normal iron parameters (serum iron, transferrin saturation, and total iron-binding capacity), absence of inflammation or liver disease, and the presence of early-onset bilateral cataracts. Definitive diagnosis is established by identifying a pathogenic variant in the FTL IRE region through molecular testing [1][2][3].
• Snippet 3 (score: 0.471) > Clinical and Molecular Clues to Diagnosing Hereditary Hyperferritinemia-Cataract Syndrome: Case Report and Literature Review

[3] Ferritin light chain gene mutations in two Brazilian families with hereditary hyperferritinemia-cataract syndrome

• Authors: R. Petroni, Susana Elaine Alves da Rosa, Flavia Pereira de Carvalho, R. Santana, J. E. Hyppolito et al.
• Year: 2017
• Venue: Einstein
• URL: https://www.semanticscholar.org/paper/7d3f0de34a2a255ad28fbd327c047996016f883a
• DOI: 10.1590/S1679-45082017RC4006
• PMID: 28746593
• PMCID: 5875167
• Citations: 2
• Summary: For the definitive diagnosis of Hereditary hyperferritinemia-cataract syndrome, the affected patients, their parents and siblings were submitted to Sanger sequencing of the 5’UTR region for detection of the ferritin light gene mutation.
• Evidence snippets:
• Snippet 1 (score: 0.580) > Hyperferritinemia-cataract syndrome is a rare disease caused by mutations in the 5'UTR region of the FTL gene. While the prevalence of this syndrome has been estimated to be approximately 1/200,000 in Australia, (8) it is unknown in Brazil. Its clinical manifestations are congenital cataract and persistent hyperferritinemia, not associated with iron overload. Several frequent conditions are associated with congenital cataract, (5) and because of that, the search for mutation in the FTL gene is rarely included in the evaluation of congenital cataract, and most patients affected by this syndrome end up being evaluated by hyperferritinemia. As mutations in the HFE gene associated with hemochromatosis are frequent in our population, (7,(9)(10)(11) this is often the main presumptive diagnosis for these patients. The HFE gene is located on 6p22.2 and encodes a membrane protein that is thought to control iron absorption, by regulating the interaction of the transferrin receptor with transferrin. Mutations in this gene cause hereditary hemochromatosis, a recessive genetic disorder,

[4] Molecular genetics of age-related cataract.

• Authors: J. Hejtmancik, M. Kantorow
• Year: 2004
• Venue: Experimental eye research
• URL: https://www.semanticscholar.org/paper/645a402e8ba9a493f728af95c3f53c168d8a4e4f
• DOI: 10.1016/J.EXER.2004.03.014
• PMID: 15183095
• Citations: 141
• Influential citations: 5
• Summary: Advances in molecular biological and genetic technology have greatly accelerated elucidation of the genetic contribution to age-related cataract. Epidemiological studies have documented tendencies for cataracts to occur more frequently in relatives of cataract patients than in the general population, genetic studies have demonstrated contributory roles of some specific genes in age related cataract in small populations, and molecular studies have shown changes in expression of specific genes...
• Evidence snippets:
• Snippet 1 (score: 0.565) > In addition to epidemiological evidence implicating genetic factors in age-related cataract, a number of inherited cataracts with post-infantile age of onset or progression of the opacity throughout life have been described. Mutations in BFSP2 can cause juvenile cataracts (Conley et al., 2000), the Marner and Volkmann cataracts can be progressive (Eiberg et al., 1995;Marner et al., 1989), mutations in aquaporin 0 (MIP) and γC-crystallin can cause progressive cataracts (Francis et al., 2000a;Ren et al., 2000), and the CAAR locus is linked to familial adult onset pulverulent cataracts (Heon et al., 2001). These all suggest that for at least some genes, a mutation that severely disrupts the protein or inhibits its function might result in congenital cataracts inherited in a highly penetrant Mendelian fashion, while a mutation that causes less severe damage to the same protein or impairs its function only mildly might contribute to age-related cataracts in a more complex multifactorial fashion. Similarly, mutations that severely disrupt the lens cell architecture or environment might produce congenital cataracts, while others that cause relatively mild disruption of lens cell homeostasis might contribute to age-related cataract. > The hyperferritinemia-cataract syndrome is a recently described disorder in which cataracts are associated with hyperferritinemia without iron overload (Beaumont et al., 1995). Ferritin L levels in the lens can increase dramatically. The molecular pathology lies in the Ferritin L iron responsive element, a stem loop structure in the 5′ untranslated region of the ferritin mRNA. Normally, this structure binds a cytoplasmic protein, the iron regulatory protein, which then inhibits translation of ferritin mRNA, which may exist in the lens at levels approaching that of a lens crystallin. Mutation of this structure and overexpression of ferritin by loss of translational control in the hyperferritinemia-cataract syndrome results in crystallization of ferritin in the lens, and other tissues as well. Ferritin

[5] Hyperferritinemia without iron overload in patients with bilateral cataracts: a case series

• Authors: Arne Kröger, E. Bachli, Andrew D. Mumford, Christoph Gubler
• Year: 2011
• Venue: Journal of Medical Case Reports
• URL: https://www.semanticscholar.org/paper/3dcfd7ab8c67377837188f0b1d30dcd9424fe726
• DOI: 10.1186/1752-1947-5-471
• PMID: 21936912
• PMCID: 3189149
• Citations: 1
• Influential citations: 1
• Summary: Hereditary hyperferritinemia cataract syndrome should be considered in all patients with unexplained hyperferritinemia without signs of iron overload, particularly those with juvenile bilateral cataracts.
• Evidence snippets:
• Snippet 1 (score: 0.524) > Hereditary hyperferritinemia cataract syndrome (HHCS) is a rare autosomal dominant genetic disease, which was first described in 1995 independently by the groups of Bonneau [1] and of Girelli [2]. They reported two families in whom elevated serum L-ferritin concentration without iron overload, presenting with juvenile bilateral cataracts, was inherited as an autosomal dominant trait [1,2]. Cataracts comprise crystalline deposits of L-ferritin. The underlying molecular defect in both the early reports of HHCS was identified as point mutations in the 5' untranslated region (5'UTR) of the L-ferritin gene (FTL), in the region corresponding to the iron-responsive element (IRE) of L-ferritin messenger ribonucleic acid (mRNA) [3,4]. These mutations lead to loss of suppression of L-ferritin mRNA translation by the iron-dependent iron regulatory protein (IRP) leading to dysregulated expression of the L-ferritin protein. Since these early reports, a series of other point mutations and short deletions of L-ferritin IRE associated with HHCS have been reported. > In 2000, Rososchova et al. measured serum ferritin concentrations in 135 Swiss patients with bilateral operated cataracts before the age of 51 to detect HHCS. However, no patients with HHCS were identified. This led those authors to postulate that HHCS is so rare that it might not exist in Switzerland [5]. We describe, to the best of our knowledge, the first two cases of HHCS in Switzerland, both with proven mutations in FTL. We also review key aspects of the metabolism of cellular iron and ferritin synthesis and we discuss the pathophysiology of HHCS.

[6] Hereditary hyperferritinemia-cataract syndrome: a case report

• Authors: Hortência Morais, Yan Haddah, M. Mota, Adriana Ferreira, M. Lacordia et al.
• Year: 2023
• Venue: Residência Pediátrica
• URL: https://www.semanticscholar.org/paper/f3c75e99245e3e3526610a308ac6e35bf6834c2d
• DOI: 10.25060/residpediatr-2023.v13n2-533
• Citations: 2
• Summary: A case of SHHC in a healthy preschooler is reported, in which the finding of elevated ferritin was obtained in an occasional test, and its variable penetrance can make it difficult to perceive the hereditary character.
• Evidence snippets:
• Snippet 1 (score: 0.495) > Hereditary hyperferritinemia-cataract syndrome: a case report

[7] Inherited cataracts: molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches

• Authors: V. Berry, M. Georgiou, K. Fujinami, R. Quinlan, A. Moore et al.
• Year: 2020
• Venue: British Journal of Ophthalmology
• URL: https://www.semanticscholar.org/paper/ffd6042f7542219ccae610d1589a703f96731754
• DOI: 10.1136/bjophthalmol-2019-315282
• PMID: 32217542
• Citations: 71
• Influential citations: 1
• Summary: The variable cataract phenotypes and molecular mechanisms, including genotype–phenotype correlations, are detailed, and future novel therapeutic avenues including cellular therapies and pharmacological treatments are explored.
• Evidence snippets:
• Snippet 1 (score: 0.477) > Cataract is the most common cause of blindness in the world; during infancy and early childhood, it frequently results in visual impairment. Congenital cataracts are phenotypically and genotypically heterogeneous and can occur in isolation or in association with other systemic disorders. Significant progress has been made in identifying the molecular genetic basis of cataract; 115 genes to date have been found to be associated with syndromic and non-syndromic cataract and 38 disease-causing genes have been identified to date to be associated with isolated cataract. In this review, we briefly discuss lens development and cataractogenesis, detail the variable cataract phenotypes and molecular mechanisms, including genotype–phenotype correlations, and explore future novel therapeutic avenues including cellular therapies and pharmacological treatments.

[8] Case Report: Identification of a CRYGD variant in a family with congenital cataract

• Authors: Junjie Deng, Jianli Ma, Yixiao Li, Wenjing Wang, Chunli Ma et al.
• Year: 2026
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/becc27fc02999449edc889411a74c86835e7e732
• DOI: 10.3389/fmed.2026.1778174
• PMID: 42359092
• PMCID: 13290538
• Summary: This case may provide useful evidence for future variant interpretation and genetic counseling in congenital cataract families carrying CRYGD variants; however, further functional studies are required to clarify the pathogenic significance of c.391T>C (p.Trp131Arg).
• Evidence snippets:
• Snippet 1 (score: 0.472) > Congenital cataract is defined as lens opacity present at birth or developing during early infancy. Although congenital cataract is relatively uncommon in the general population, it is an important cause of preventable visual impairment in children worldwide (1). Epidemiological studies indicate that the prevalence of congenital cataract varies across populations, and genetic factors make a substantial contribution to its etiology. In hereditary cases, autosomal dominant inheritance is the most common pattern, although autosomal recessive and X-linked forms have also been reported (2)(3)(4)(5). > The molecular mechanisms underlying hereditary cataract are heterogeneous. Mutations in genes encoding lens structural proteins, membrane proteins, cytoskeletal proteins, transcription factors, and other developmental regulators have all been implicated. Among these, crystallin genes are among the most frequently reported disease-associated genes. CRYGD encodes γD-crystallin, a major structural protein that is essential for maintaining lens transparency and refractive properties (6,7). Variants in CRYGD have been associated with autosomal dominant congenital cataract in multiple populations (8)(9)(10)(11). > Recent studies have further confirmed the marked genetic heterogeneity of congenital cataract. In a 2025 cohort of 19 Chinese families with congenital cataract, WES followed by Sanger-based co-segregation analysis identified likely pathogenic variants in several cataract-associated genes, including CRYGD, GJA3, CRYAA, CRYBA1, BFSP2, IARS2, ARL2, and CRYBB3, with additional variants classified as VUS. Another 2025 study of 114 probands with congenital cataract also demonstrated broad genotype-phenotype heterogeneity involving isolated cataract, cataract with additional ocular anomalies, and cataract with multisystem abnormalities, supporting the value of WES for variant screening and genotype-phenotype correlation analysis in congenital cataract (12,13). > Despite substantial progress in identifying disease-related genes, the clinical interpretation of individual rare variants remains challenging, particularly when functional validation is unavailable.

[9] Hereditary Hyperferritinemia Cataract Syndrome: Case Report

• Authors: Unknown authors
• Year: 2020
• Venue: Gazi Medical Journal
• URL: https://www.semanticscholar.org/paper/a17f28fc79fce49e5d8c0174459472ac53ecf0d3
• DOI: 10.12996/gmj.2020.108
• Summary: Hereditary Hyperferritinemia-Cataract Syndrome (HHCS) is a rare disease characterized by cataract and hyperferritinemia. Herein, we present a pediatric patient diagnosed with HHCS.
• Evidence snippets:
• Snippet 1 (score: 0.471) > Hereditary Hyperferritinemia Cataract Syndrome: Case Report

[10] [Hereditary syndrome of hyperferritinemia and cataract].

• Authors: J. Andonegui, M. Prat, M. Vargas
• Year: 2007
• Venue: Anales del sistema sanitario de Navarra
• URL: https://www.semanticscholar.org/paper/1bad42e41c1c8c6f277590f194cead7be0dbb4ed
• DOI: 10.23938/ASSN.0214
• PMID: 17898822
• Citations: 2
• Influential citations: 1
• Summary: This report describes a family with hereditary hyperferritinemia cataract syndrome, whose clinical characteristics are familial cataracts of early development and elevated serum ferritin levels but otherwise normal iron studies and haematological parameters.
• Evidence snippets:
• Snippet 1 (score: 0.462) > [Hereditary syndrome of hyperferritinemia and cataract].

[11] Congenital cataract – clinical and morphological aspects

• Authors: C. Tătaru, C. Tătaru, A. Costache, O. Borugă, M. Zemba et al.
• Year: 2020
• Venue: Romanian Journal of Morphology and Embryology
• URL: https://www.semanticscholar.org/paper/931a9bc039759d81bd94cc0560669b27263ef913
• DOI: 10.47162/RJME.61.1.11
• PMID: 32747900
• PMCID: 7728133
• Citations: 20
• Summary: Clinically, the most frequent was the total cataract, followed by lamellar, nuclear and cerulean, and Morphologically, obvious changes were rendered evident at the level of anterior and posterior capsules, as well as subcapsular.
• Evidence snippets:
• Snippet 1 (score: 0.458) > Congenital cataract is a major cause of visual impairment in children [1]. It may occur as a single condition or in association with other ocular, somatic or neuropsychiatric disorders [6,12]. Congenital cataract identified at birth or in the first decade rises many unknown issues, henceforth their multiple clinical aspects [13]. > Congenital cataract is hereditary, up to 25% of the cases, of which 75% are autosomal dominant [14,15]. Today, 115 genes associated to syndromic and nonsyndromic cataract were found, while 38 genes were identified as causes of a cataract-associated disease [6]. > Genetic mutation affects various components in the lens structure. According to Shiels & Hejtmancik (2017), about 45% of the genetic mutations have an impact on crystallin proteins, about 16% of genetic mutations affect connexins, 12% act on growth and transcription factors, while 8% on metabolism, including the lipid metabolism [11]. The great clinical variety of congenital cataract is accounted for by the fact that the same genetic mutation generates radically different cataract phenotypes in different families; while differing genetic mutations can trigger similar morphological cataracts, which suggests that, apart from genetic mutations, there are additional factors, i.e., potential environmental factors that are involved in morphological variety [11]. > "Crystallins" represent over 90% of the soluble proteins existing in the human lens structure. They have a great importance in maintaining the refraction index in the lens [16]. In the human lens three main classes of "crystallins" have been identified, i.e., α-crystallin -representing 40%, β-crystallin -about 35% and γ-crystallin -25% [5,17,18]. > Mutations of genes codifying "crystallins" and "connexins" are found in congenital cataract, not associated with genetic syndromes, while mutations of α-crystallin lead to lamellar, nuclear and posterior polar cataract. > In literature, lamellar congenital cataract is thought to be the most frequently encountered form of cataract in pediatric patients [19].

[12] Hereditary Hyperferritinemia Cataract Syndrome: Ferritin L Gene and Physiopathology behind the Disease—Report of New Cases

• Authors: Ferran Celma Nos, G. Hernández, X. Ferrer-Cortès, I. Hernández-Rodríguez, B. Navarro-Almenzar et al.
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/86b7c413f341ca6126ece14696f788f3c810eb75
• DOI: 10.3390/ijms22115451
• PMID: 34064225
• PMCID: 8196845
• Citations: 13
• Influential citations: 1
• Summary: Two new families affected with hereditary hyperferritinemia-cataract syndrome with previous known mutations are reported, and it is important to test serum ferritin levels in patients with cataracts.
• Evidence snippets:
• Snippet 1 (score: 0.457) > Hereditary Hyperferritinemia Cataract Syndrome: Ferritin L Gene and Physiopathology behind the Disease—Report of New Cases

[13] Hyperferritinaemia-cataract syndrome: Worldwide mutations and phenotype of an increasingly diagnosed genetic disorder

• Authors: G. Millonig, M. Muckenthaler, S. Mueller
• Year: 2010
• Venue: Human Genomics
• URL: https://www.semanticscholar.org/paper/6e851cf11d3b9dff5f9f4a8b66465212861800ea
• DOI: 10.1186/1479-7364-4-4-250
• PMID: 20511138
• PMCID: 3525215
• Citations: 49
• Influential citations: 4
• Summary: Haematologists, gastroenterologists and ophthalmologists should be aware of this syndrome to spare patients from further invasive diagnosis (liver biopsy), and also from a false diagnosis of hereditary haemochromatosis followed by venesections.
• Evidence snippets:
• Snippet 1 (score: 0.457) > Hyperferritinaemia-cataract syndrome: Worldwide mutations and phenotype of an increasingly diagnosed genetic disorder

[14] Whole Exome Sequencing of 20 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Cataracts

• Authors: Patricia Rodríguez-Solana, N. Arruti, M. Nieves-Moreno, R. Mena, Carmen Rodríguez-Jiménez et al.
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/8994a40a92f05aa1e83481e02a7baecbf8e11348
• DOI: 10.3390/ijms241411429
• PMID: 37511188
• PMCID: 10380485
• Citations: 10
• Summary: LONP1, ACACA, TRPM1, CLIC5, HSPE1, ODF1, PIKFYVE, and CHMP4A are proposed as potential candidates to further investigate for their role in pediatric cataracts, and AQP5 and locus 2q37 as causal genes are proposed.
• Evidence snippets:
• Snippet 1 (score: 0.457) > Congenital cataracts were the first disease with autosomal dominant inheritance mapped in humans [17]. Although this pattern of inheritance predominates in pediatric cataracts of hereditary origin, autosomal recessive [18] and X-linked [19] patterns of inheritance have also been reported. > Non-syndromic congenital cataracts typically have complete penetrance, with autosomal dominant cataracts more common than recessive cataracts. Their expressivity is highly variable; thus, the same mutation within an affected family can give rise to various phenotypes. Furthermore, it is possible that the same type of cataract can be caused by mutations at different loci, making it a polygenic disease [6]. This complicated genotype-phenotype correlation complicates the genetic diagnosis of patients. > Currently, some 71 loci mapped to 56 cataract-causing genes have been identified [20]. This information is recorded in Cat-Map, a database that presents a chromosomal map together with the spectrum of mutations associated with hereditary cataracts, updated in real time [21]. The genetic causes of Mendelian cataracts can be grouped according to the cellular processes affected, suggesting that these pathways are critical for the correct development or homeostasis of the lens. Thus far, the most frequently implicated genes are those for crystallins (33%), developmental or transcription factors (26%), connexins (18%), membrane proteins and transporters (11%), genes involved in lipid metabolism (8%), and intermediate filament and chaperone proteins (4%) [20].

[15] Hereditary Hyperferritinemia-Cataract Syndrome Misdiagnosed as Iron Overload: A Case Report

• Authors: Serkan Güven, Menekşe Öztürk
• Year: 2026
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/3dd18039331ae262633475c1852ad650a8e54ced
• DOI: 10.7759/cureus.102469
• PMID: 41769540
• PMCID: 12947710
• Summary: The case of a 58-year-old male patient with longstanding unexplained hyperferritinemia, normal transferrin saturation, and a striking multigenerational family history of early-onset cataracts, highlights a critical diagnostic pitfall in hematology practice and emphasizes the importance of interpreting serum ferritin in conjunction with transferrin saturation.
• Evidence snippets:
• Snippet 1 (score: 0.457) > A 58-year-old male patient was referred to our hematology clinic for evaluation of persistent hyperferritinemia of unknown origin. Hyperferritinemia had been present for a long time according to the patient's history, although the exact duration was unknown. A single session of therapeutic phlebotomy was performed due to suspected iron overload and an elevated hemoglobin level. His medical history was notable for bilateral cataracts, first diagnosed in the fifth decade of life, which showed gradual progression and ultimately required bilateral cataract surgery. Family history revealed multiple affected relatives, including his father, five sisters, his daughter, and a grandchild, all of whom had early-onset cataracts accompanied by elevated ferritin levels, suggesting an autosomal dominant inheritance pattern. A detailed multigenerational pedigree diagram could not be constructed due to the incomplete availability of clinical and genetic information from all affected family members. Nevertheless, the observed vertical transmission across successive generations strongly supports an autosomal dominant inheritance pattern. > Physical examination was unremarkable, with no clinical signs suggestive of iron overload. Laboratory evaluation revealed a hemoglobin level of 15.7 g/dL, a white blood cell count of 7.78 × 10⁹/L, a platelet count of 156 × 10⁹/L, and a mean corpuscular volume of 90.5 fL. Enzyme-linked immunosorbent assay-based viral serologies, including hepatitis B surface antigen, anti-hepatitis C virus antibody, and HIV testing, were all negative. Serum ferritin was markedly elevated at 790 µg/L (reference range 23-333 µg/L). In contrast, serum iron concentration, transferrin saturation, liver function tests, and C-reactive protein levels were within normal limits, excluding iron overload, hepatic disease, and inflammation-related hyperferritinemia (Table 1). Abdominal ultrasonography demonstrated no hepatomegaly or evidence of hepatic iron deposition. The patient reported no history of alcohol consumption. Because of suspected hereditary hemochromatosis, a single session of therapeutic phlebotomy was performed prior to referral.

[16] L-Ferritin: One Gene, Five Diseases; from Hereditary Hyperferritinemia to Hypoferritinemia—Report of New Cases

• Authors: B. Cadenas, Josep Fita-Torró, M. Bermúdez-Cortés, I. Hernández-Rodríguez, J. Fuster et al.
• Year: 2019
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/06a1aed362cacb43ebc25546c5b3b4fd921957cd
• DOI: 10.3390/ph12010017
• PMID: 30678075
• PMCID: 6469184
• Citations: 28
• Influential citations: 1
• Summary: A diagnostic algorithm is included for the detection of diseases caused by defects in FTL gene that cause dominant L-ferritin deficiency and HHCS and one previously reported variant (Met1Val) that causes dominant L+2T deficiency.
• Evidence snippets:
• Snippet 1 (score: 0.450) > According to our bioinformatics prediction, the c.375 + 2T > A mutation will not generate a dominant-negative version of FTL protein, but a truncated FTL protein completely missing the E-α-helix domain and partially lacking the D-α-helix domain. Supported by the clinical manifestations found in this family (low serum ferritin levels, low transferrin saturation and lack of serious neurological or movement abnormalities), the molecular mechanism in this case is most probably due to the loss of function of FTL and it will be not expected that the disease derives in neuroferritinopathy. However, we cannot totally and completely exclude the later development in life of brain iron overload and neuroferritinopathy in these patients by a yet unknown and novel mechanism. > Patients with hereditary hyperferritinemia could be misdiagnosed as patients suffering from hereditary hemochromatosis, liver dysfunction or inflammation. Some patients have received unnecessary invasive diagnostic techniques, such as liver biopsy, and are inappropriately treated with venesections and phlebotomies that can cause severe iron-deficiency anemia. On the other hand, clinical manifestations of neuroferritinopathy including tremor, parkinsonism, psychiatric problems, and abnormal involuntary movements, the presence of ferritin-iron precipitation in glia cells and neurons [30], are often misdiagnosed and treated as Huntington's or Parkinson's disease. Potential treatment targets for neuroferritinopathy may include an optimized iron chelator to induce the re-solubilization of iron aggregations, in combination with radical scavengers to prevent oxidative ferritin damage [35]. Patients with benign hyperferritinemia could be misdiagnosed as patients with HHCS due to the presence of high ferritin levels and the possible late-onset appearance of cataracts. Apart from the surgical removal of cataracts in HHCS, HHCS and L-ferritin deficiency have no specific therapy. > These facts emphasize the importance of a correct and early genetic diagnosis for the subsequent implementation of proper treatment, avoiding detrimental or inappropriate treatments.

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