{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T06:41:38Z","timestamp":1777444898354,"version":"3.51.4"},"reference-count":29,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T00:00:00Z","timestamp":1687737600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Biochem"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:p>Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal disorder characterized by the proliferation and infiltration of macrophages and hyperactivated T lymphocytes that escape from the physiological control pathways and favour the existence of an environment of excessive inflammation and tissue destruction. HLH has been classified into two types: a primary or familial autosomal recessive form, caused by mutations in genes encoding proteins involved in the granule-dependent cytotoxic pathway (familial hemophagocytic lymphohistiocytosis [FHL] types 1\u20135); and other secondary or acquired form, generally associated with infections, malignancy, autoimmune diseases, metabolic disorders or primary immunodeficiencies. Since the first familial hemophagocytic lymphohistiocytosis-2 (FHL2) causative mutation in the PRF1 gene was described in 1999, more than 200 mutations have been identified to date. Here, we report the first case of very late-onset FHL2 in a Spanish 72-year-old female with splenomegaly, hypertriglyceridemia, hypofibrinogenemia, pancytopenia and marrow hemophagocytosis harbouring in heterozygosity two PRF1 variants proposed as causative in this study. The heterozygous mutation c.445G&gt;A (p.Gly149Ser) identified in the exon 2 results in a missense mutation previously described as a probable pathogenic variant associated with the development of FHL2. Affecting the same exon, c.272C&gt;T (p.Ala91Val) is the most prevalent variant of this gene. Although it was initially classified as benign, recent studies support its potential pathogenic role, considering it a variant of uncertain significance associated with a risk of developing FHL2. The genetic confirmation of FHL made possible an adequate counselling to the patient and direct relatives and provided important information for her control and follow-up.<\/jats:p>","DOI":"10.1177\/00045632231186076","type":"journal-article","created":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T01:58:24Z","timestamp":1687831104000},"page":"356-364","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["First case of very late-onset FHL2 in Spain with two variants in the PRF1 gene"],"prefix":"10.1177","volume":"60","author":[{"given":"Paula","family":"Sienes Bailo","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry and Clinical Genetics, Hospital Universitario Miguel Servet, Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1732-4883","authenticated-orcid":false,"given":"Nuria","family":"Go\u00f1i Ros","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Clinical Genetics, Hospital Universitario Miguel Servet, Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00e1rbara","family":"Men\u00e9ndez J\u00e1ndula","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hospital Universitario Miguel Servet, Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramiro","family":"\u00c1lvarez Alegret","sequence":"additional","affiliation":[{"name":"Department of Pathologic Anatomy, Hospital Universitario Miguel Servet, Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"Gonz\u00e1lez G\u00f3mez","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hospital Universitario Miguel Servet, Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo","family":"Gonz\u00e1lez Taranc\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Clinical Genetics, Hospital Universitario Miguel Servet, Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Izquierdo \u00c1lvarez","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Clinical Genetics, Hospital Universitario Miguel Servet, Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2023,6,26]]},"reference":[{"key":"bibr1-00045632231186076","doi-asserted-by":"publisher","DOI":"10.3928\/19382359-20170717-01"},{"issue":"2","key":"bibr2-00045632231186076","first-page":"71","volume":"53","author":"Porras O","year":"2011","journal-title":"Acta Med Costarric"},{"key":"bibr3-00045632231186076","unstructured":"McClain KL, Eckstein O. 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Familial hemophagocytic lymphohistiocytosis [Internet]. 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