Letter to the Editor
Hemophagocytic lymphohistiocytosis secondary to X-linked lymphoproliferative syndrome type 2
Linfohistiocitosis hemofagocítica secundaria a síndrome linfoproliferativo ligado al cromosoma X tipo 2
Pedro Laguna del Estal
, Amy Galán Gómez, Sonia García Prieto
Corresponding author
Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
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It presents with fever, hepatosplenomegaly, lymphadenopathy, cytopenia, and characteristic laboratory (hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia), immunological (reduced NK activity, elevated CD25s) and pathological (hemophagocytosis in bone marrow or spleen) abnormalities; these clinical–biological data are used as diagnostic criteria. HLH can be sporadic or hereditary. In a recent series, 44% were hereditary.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Of these, 76% were due to mutations in familial HLH (FHL) genes; 16% resulted from mutations causing immunodeficiency, such as Griscelli syndrome, Chédiak–Higashi syndrome, X-linked lymphoproliferative syndrome type 1 (SLX-1) and type 2 (SLX-2); and 8% showed no genetic alterations. We report a case of HLH associated with SLX-2 (OMIM #300635), the first in Spain, diagnosed in adulthood.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 35 year-old male with repeated episodes of fever and splenomegaly (the first at 3 months of age) with no aetiological diagnosis. Admitted for fever of 39 °C, vomiting and diarrhoea. On examination, splenomegaly was observed. Laboratory tests on admission highlighted the following: 760 neutrophils/mm<span class="elsevierStyleSup">3</span>, 56,000 platelets/mm<span class="elsevierStyleSup">3</span>, ALT 392 U/L, AST 284 U/L, LDH 1742 U/L, ferritin 17,030 ng/mL, triglycerides 392 mg/dL; IgG, IgA, IgM and IgD values were normal. Stool microbiological studies, blood cultures, serology, and PCR for EBV and CMV were negative. A computed tomography scan revealed hepatosplenomegaly and retroperitoneal and mesenteric lymphadenopathy. Symptomatology subsided without specific treatment and the patient was discharged. At a 3 month check-up he was asymptomatic, with normal blood tests and an ultrasound splenomegaly of 14 cm. Hereditary HLH was studied (FHL types 2–5, Griscelli syndrome, SLX-1, and SLX-2). A hemizygous mutation consisting of a transition from a C to a T (c.664C> T) was detected in the BIRC4 gene, which at the level of the X-linked apoptosis inhibitor protein (XIAP) produces the change of an arginine from position 222 to a premature stop codon (p.R222*), a causative mutation of SLX-2. The mutation was also detected in the mother, who had never had any symptoms, but not in her only female sibling. At 16 months he was admitted with similar clinical features; hemophagocytosis was not observed in the bone marrow aspirate. He received immunoglobulin treatment (0.5 mg/kg) and dexamethasone (40 mg/day/5 days, 20 mg/day/4 days), with good response.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Initially described in 2006, the SLX-2 has an incidence of 1/10<span class="elsevierStyleSup">6</span> males and causes 2% of hereditary HLH.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Aguilar and Latour<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> analysed 100 cases reported up to 2015. The most common clinical manifestations were: splenomegaly associated with fever and cytopenia (57%); HLH (54%), triggered by EBV in 66% of cases; inflammatory bowel disease (26%), similar to Crohn’s disease; hypogammaglobulinemia (16%); other inflammatory manifestations<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> (7%), including arthritis, skin abscesses, erythema nodosum, uveitis, and nephritis. Each of the above phenotypes can occur in isolation in patients, although they usually present at least 2 phenotypes, which may not coincide temporally. Affected members of the same family may have significant differences in phenotype (HLH vs. Crohn’s disease) and severity (asymptomatic vs. fatal) of the disease. Women can transmit the disease to their male children but remain asymptomatic as a consequence of the random inactivation of one of the alleles of the BIRC4 gene. However, exceptionally, women with SLX-2 symptoms due to a biased inactivation of the healthy gene have been reported.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The diagnosis can only be confirmed by genetic study, detecting some of the described pathogenic genetic alterations in the BIRC4 gene. Flow cytometry can also be used to determine the absence of XIAP activity in peripheral blood mononuclear cells, but this technique may give false negatives in patients with mutations that allow residual expression of the protein.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Treatment will be adjusted to the clinical phenotype: HLH, Crohn’s disease, hypogammaglobulinemia, etc. The only curative treatment is hematopoietic stem cell transplantation, but it should be reserved for the most severe cases that do not respond to conventional treatment, since the procedure is associated with high mortality (63%), especially in cases with active HLH at the time of transplant and if reduced intensity conditioning regimens are not used. In 2015, 22 of the 100 cases reported died<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>: 4 from HLH, 4 from Crohn’s disease, one from pneumonia, one from liver failure, and 12 during transplantation; exceptionally, some patients remained asymptomatic (identified in the familial study). Such extreme variety in the course of the disease, together with the different phenotypic expression by which it can manifest itself, means that treatment must be individualised.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Laguna del Estal P, Galán Gómez A, García Prieto S. Linfohistiocitosis hemofagocítica secundaria a síndrome linfoproliferativo ligado al cromosoma X tipo 2. Med Clin (Barc). 2020. <span class="elsevierStyleInterRef" id="intr0005" href="https://doi.org/10.1016/j.medcli.2020.05.043">https://doi.org/10.1016/j.medcli.2020.05.043</span></p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.I. Henter" 1 => "A. Horne" 2 => "M. Aricó" 3 => "R.M. Egeler" 4 => "A.H. Filipovich" 5 => "S. 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Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/pbc.25483" "Revista" => array:6 [ "tituloSerie" => "Pediatr Blood Cancer" "fecha" => "2015" "volumen" => "62" "paginaInicial" => "1288" "paginaFinal" => "1290" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25801017" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015700000004/v2_202201010719/S238702062100365X/v2_202201010719/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015700000004/v2_202201010719/S238702062100365X/v2_202201010719/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S238702062100365X?idApp=UINPBA00004N" ]
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