{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T19:02:53Z","timestamp":1784055773023,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Brazilian National Program","award":["25000.193451\/2019-21"],"award-info":[{"award-number":["25000.193451\/2019-21"]}]},{"name":"Brazilian National Program","award":["IFF-002-FEX-22"],"award-info":[{"award-number":["IFF-002-FEX-22"]}]},{"name":"Foundation for the scientific and technological development in health","award":["25000.193451\/2019-21"],"award-info":[{"award-number":["25000.193451\/2019-21"]}]},{"name":"Foundation for the scientific and technological development in health","award":["IFF-002-FEX-22"],"award-info":[{"award-number":["IFF-002-FEX-22"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare, frequently misdiagnosed, autosomal dominant disease caused by mutations in the FTL gene. It causes bilateral pediatric cataract and hyperferritinemia without iron overload. The objective of this case series, describing three Brazilian families, is to increase awareness of HHCS, as well as to discuss possible phenotypic interactions with concurrent mutations in HFE, the gene associated with autosomal recessive inheritance hereditary hemochromatosis. Whole-exome sequencing was performed in eight individuals with HHCS from three different families, as well as one unaffected member from each family for trio analysis\u2014a total of eleven individuals. Ophthalmological and clinical genetic evaluations were conducted. The likely pathogenic variant c.-157G&gt;A in FTL was found in all affected individuals. They presented slowly progressing bilateral cataract symptoms before the age of 14, with a phenotype of varied bilateral diffuse opacities. Hyperferritinemia was present in all affected members, varying from 971 ng\/mL to 4899 ng\/mL. There were two affected individuals with one concurrent pathogenic variant in HFE (c.187C&gt;G, p.H63D), who were also the ones with the highest values of serum ferritin in our cohort. Few publications describe individuals with pathogenic mutations in both FTL and HFE genes, and further studies are needed to assess possible phenotypic interactions causing higher values of hyperferritinemia.<\/jats:p>","DOI":"10.3390\/ijms241511876","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T01:21:27Z","timestamp":1690248087000},"page":"11876","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genotypic\u2013Phenotypic Correlations of Hereditary Hyperferritinemia-Cataract Syndrome: Case Series of Three Brazilian Families"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7704-3450","authenticated-orcid":false,"given":"Olivia A.","family":"Zin","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, Brazil"},{"name":"Instituto Brasileiro de Oftalmologia, Rio de Janeiro 22250-040, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2305-2853","authenticated-orcid":false,"given":"Luiza M.","family":"Neves","sequence":"additional","affiliation":[{"name":"Instituto Fernandes Figueira-Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil"},{"name":"Department of Ophthalmology, Universidade do Estado do Rio de Janeiro, Rio de janeiro 20551-030, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela P.","family":"Cunha","sequence":"additional","affiliation":[{"name":"Instituto Fernandes Figueira-Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2230-995X","authenticated-orcid":false,"given":"Fabiana L.","family":"Motta","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica Ocular, S\u00e3o Paulo 04552-050, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna N. S.","family":"Agonigi","sequence":"additional","affiliation":[{"name":"Instituto Fernandes Figueira-Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafne D. G.","family":"Horovitz","sequence":"additional","affiliation":[{"name":"Instituto Fernandes Figueira-Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Daltro C.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Instituto Fernandes Figueira-Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocieli","family":"Malacarne","sequence":"additional","affiliation":[{"name":"Instituto Fernandes Figueira-Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Paula S.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana B.","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Cardiologia, Rio de Janeiro 22240-006, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinthia A.","family":"Rivello","sequence":"additional","affiliation":[{"name":"Instituto Brasileiro de Oftalmologia, Rio de Janeiro 22250-040, Brazil"},{"name":"Instituto Catarata Infantil, Rio de Janeiro 22250-040, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Espariz","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hospital Federal Cardoso Fontes, Rio de Janeiro 22745-130, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7677-0034","authenticated-orcid":false,"given":"Andrea A.","family":"Zin","sequence":"additional","affiliation":[{"name":"Instituto Brasileiro de Oftalmologia, Rio de Janeiro 22250-040, Brazil"},{"name":"Instituto Fernandes Figueira-Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil"},{"name":"Instituto Catarata Infantil, Rio de Janeiro 22250-040, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7206-4447","authenticated-orcid":false,"given":"Juliana M. F.","family":"Sallum","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04039-032, Brazil"},{"name":"Instituto de Gen\u00e9tica Ocular, S\u00e3o Paulo 04552-050, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2193-2224","authenticated-orcid":false,"given":"Zilton F. M.","family":"Vasconcelos","sequence":"additional","affiliation":[{"name":"Instituto Fernandes Figueira-Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1136\/jmg.32.10.778","article-title":"Bilateral cataract and high serum ferritin: A new dominant genetic disorder?","volume":"32","author":"Bonneau","year":"1995","journal-title":"J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1111\/j.1365-2141.1995.tb05218.x","article-title":"A linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract","volume":"90","author":"Girelli","year":"1995","journal-title":"Br. J. Haematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/S0002-9394(01)01106-0","article-title":"Lens Changes in Hereditary Hyperferritinemia\u2013Cataract Syndrome","volume":"132","author":"Ades","year":"2001","journal-title":"Am. J. Ophthalmol."},{"key":"ref_4","unstructured":"(2023, May 22). Cat-Map. Available online: https:\/\/cat-map.wustl.edu\/."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1001\/archopht.121.12.1753","article-title":"Hereditary Hyperferritinemia-Cataract Syndrome\u2014Prevalence, lens morphology, spectrum of mutations and clinical presentations","volume":"121","author":"Craig","year":"2003","journal-title":"Arch. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1080\/08880018.2019.1621972","article-title":"Elevated serum ferritin level with cataract of spectacular morphology: Hyperferritinemia cataract syndrome","volume":"36","author":"Aslan","year":"2019","journal-title":"Pediatr. Hematol. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1006\/bcmd.2002.0590","article-title":"Pathogenesis of hyperferritinemia cataract syndrome","volume":"29","author":"Roetto","year":"2002","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.jaapos.2007.01.126","article-title":"Hereditary hyperferritinemia-cataract syndrome","volume":"11","author":"Christiansen","year":"2007","journal-title":"J. AAPOS"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e351","DOI":"10.1016\/j.jaapos.2020.07.014","article-title":"Hereditary hyperferritinemia-cataract syndrome in three Czech families: Molecular genetic testing and clinical implications","volume":"24","author":"Moravikova","year":"2020","journal-title":"J. AAPOS"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/bs.acc.2016.03.002","article-title":"Transferrin saturation: A body iron biomarker","volume":"Volume 75","author":"Elsayed","year":"2016","journal-title":"Advances in Clinical Chemistry"},{"key":"ref_11","first-page":"333","article-title":"Management of elevated serum ferritin leves","volume":"4","author":"Adams","year":"2008","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sandnes, M., Ulvik, R.J., Vorland, M., and Reikvam, H. (2021). Hyperferritinemia\u2014A clinical overview. J. Clin. Med., 10.","DOI":"10.3390\/jcm10092008"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1136\/jcp.2010.083188","article-title":"Serum ferritin values in primary care: Are high values overlooked?","volume":"63","author":"Ogilvie","year":"2010","journal-title":"J. Clin. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.taap.2004.06.021","article-title":"Iron metabolism and toxicity","volume":"202","author":"Papanikolaou","year":"2005","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/vox.12896","article-title":"Diagnosis and management of hereditary haemochromatosis","volume":"115","author":"Murphree","year":"2020","journal-title":"Vox Sang."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nos, F.C., Hern\u00e1ndez, G., Ferrer-Cort\u00e8s, X., Hernandez-Rodriguez, I., Navarro-Almenzar, B., Fuster, J.L., Cort\u00e9s, M.B., P\u00e9rez-Montero, S., Tornador, C., and Sanchez, M. (2021). Hereditary Hyperferritinemia Cataract Syndrome: Ferritin L Gene and Physiopathology behind the Disease- Report of New Cases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115451"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.31744\/einstein_journal\/2022RC0076","article-title":"Brazilian family with hyperferritinemia-cataract syndrome: Case report","volume":"20","author":"Alvarenga","year":"2022","journal-title":"Einstein"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/j.1399-0004.2010.01517.x","article-title":"Identification of the mutations associated with hereditary hyperferritinemia cataract syndrome and hemocromatosis in a Brazilian family","volume":"79","author":"Meneses","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1590\/s1679-45082017rc4006","article-title":"Ferritin light chain gene mutations in two Brazilian families with hereditary hyperferritinemia-cataract syndrome","volume":"15","author":"Petroni","year":"2017","journal-title":"Einstein"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/ajmg.a.30425","article-title":"Identification of novel mutation in the L-ferritin IRE leading to hereditary hyperferritinemia-cataract syndrome","volume":"134A","author":"Phillips","year":"2005","journal-title":"Am. J. Med. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"26439","DOI":"10.1074\/jbc.274.37.26439","article-title":"Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome","volume":"274","author":"Allerson","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1182\/blood.V90.2.814","article-title":"Hereditary hyperferritinemia-cataract syndrome.: Relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA","volume":"90","author":"Cazzola","year":"1997","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1750-1172-8-30","article-title":"Novel Mutation in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome","volume":"8","author":"Luscieti","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1006\/jmbi.1997.1377","article-title":"Structure and Dynamics of the Iron ResponsiveElement RNA: Implications for Binding of the RNA by Iron Regulatory Binding Proteins","volume":"274","author":"Addess","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"23637","DOI":"10.1074\/jbc.273.37.23637","article-title":"Loops and bulge\/loops in iron-responsive element isoforms influence iron regulatory protein binding: Fine tuning of mRNA regulation?","volume":"273","author":"Ke","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4180","DOI":"10.1182\/blood.V91.11.4180","article-title":"Analysis of ferritins in lymphoblastoid cell lines and in the lens of subjects with hereditary hyperferritinemia-cataract syndrome","volume":"91","author":"Levi","year":"1998","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.jaapos.2011.03.020","article-title":"Hereditary hyperferritinemia-cataract syndrome in two large multigenerational American families","volume":"15","author":"Shekunov","year":"2011","journal-title":"J. AAPOS"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1136\/bjo.84.7.697","article-title":"The lens in hereditary hyperferritinaemia cataract syndrome contains crystalline deposits of L-ferritin","volume":"84","author":"Mumford","year":"2000","journal-title":"Br. J. Ophthalmol."},{"key":"ref_29","first-page":"36253","article-title":"Hereditary Hyperferritinemia-Cataract Syndrome in a Family With HFE-H63D Mutation","volume":"15","author":"Eris","year":"2023","journal-title":"Cureus"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"63","DOI":"10.12688\/f1000research.16665.2","article-title":"Sarek: A portable workflow for whole-genome sequencing analysis of germline and somatic variants","volume":"9","author":"Garcia","year":"2020","journal-title":"F1000Research"},{"key":"ref_31","unstructured":"(2023, May 01). ABraOM: Brazilian Genomic Variants. Available online: http:\/\/abraom.ib.usp.br\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/11876\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:18:18Z","timestamp":1760127498000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/11876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,25]]},"references-count":31,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241511876"],"URL":"https:\/\/doi.org\/10.3390\/ijms241511876","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,25]]}}}