Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II

Abstract

Griscelli syndrome (GS) was diagnosed in a 2-year-old patient with oculocutaneous albinism and immunodeficiency, but sequencing of RAB27a revealed only a heterozygous mutation. Due to impaired natural killer (NK) and T-cell cytotoxicity implying a high risk of developing hemophagocytic lymphohistiocytosis (HLH), he was prepared for hematopoietic stem cell transplantation (HSCT). Unexpectedly, a severe bleeding episode occurred that led to the demonstration of disturbed platelet aggregation, reduced plateletdense granules, and impaired platelet degranulation. In combination with neutropenia, this suggested the diagnosis of Hermansky-Pudlak syndrome type II (HPSII) and a novel homozygous mutation in AP3B1 was detected. None of the 3 reported HPSII patients had developed HLH, and our patient seroconverted to Epstein-Barr virus (EBV) without clinical symptoms. HSCT was therefore withheld, and granulocyte-colony-stimulating factor (G-CSF) therapy was initiated and prevented further bacterial infections. At 3 years of age, however, the patient developed, without an obvious trigger, fulminant HLH that was resistant to therapy. This patient shows that careful clinical and molecular diagnosis is essential to differentiate the complex disorders of ly- IntroductionSecretory lysosomes are cellular organelles involved in trafficking and exocytosis of intracellular proteins. 1 They have important functions in several cell types including melanocytes, neuronal cells, platelets, granulocytes, mast cells, natural killer (NK) cells, and T cells. 2 The protein machinery required for adequate biogenesis, transport, and delivery of secretory lysosomes has a variable composition in each cell type. Therefore, the clinical phenotype of diseases due to genetic defects in proteins involved in lysosomal trafficking varies widely despite the similar cell-biologic basis. This has led to their classification as predominantly dermatologic, hematologic, hemostaseologic, or immunologic disorders. While the 7 genetically defined Hermansky-Pudlak syndromes (HPSs) predominantly present as bleeding disorders, 3 the most important clinical problem of patients with Chédiak-Higashi syndrome (CHS) and Griscelli syndrome type II (GSII) is immunodeficiency. 4 Neurologic defects characterize GSI and CHS, 5 while patients with GSIII show only oculocutaneous albinism. 6 This latter feature links all of these syndromes. However, studies showing that also some forms of familial hemophagocytic lymphohistiocytosis (FHL) represent lysosomal trafficking disorders 7,8 revealed that albinism is not a constant feature in this heterogenous family of diseases.Lysosomal trafficking disorders associated with immunodeficiency are life-threatening conditions due to the high risk of developing hemophagocytic lymphohistiocytosis (HLH). 4 HLH is a systemic inflammatory disorder characterized by uncontrolled CD8 ϩ T-cell and macrophage activation with infiltration of multiple tissues. 9 The common defect in most genetic diseases predisposing to HLH is disturbed secretion of ...

Two patients with Hermansky Pudlak syndrome type 2 and novel mutations in AP3B1

“…Subject P3 also showed dysmorphia and pulmonary fibrosis that have been previously reported in HPS2, 7,[12][13][14][15] and had two episodes of hemophagocytic syndrome following common viral infections. Hemophagocytic syndrome has previously been reported in a single HPS2 patient, 15 although this patient also carried a mutation in one allele of Rab27a, a gene known to be involved in hemophagocytic syndrome. Subject P2 showed a less severe clinical phenotype than P3, possibly because of residual expression of a truncated β3A protein in P2, in contrast to absent expression in P3.…”

“…Levels of CTL cytotoxicity in P2 and P3 varied compared to the previous HPS2 patient, P1. 5 Decreased CTL and NK cell cytotoxicity has been reported for other HPS2 patients, 7,15 and the reasons for the variable levels of killing seen in clones from P2 and P3 reported here are not yet understood. The physiological implications of reduced cell-mediated cytotoxicity are seen in the recurrent bacterial and viral infections observed in these and other HPS2 patients, although the relative contributions of CTL, NK cell and neutrophil defects to this phenotype are not yet fully determined.…”

Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases

“…10 Histomorphological demonstration of hemophagocytosis in the bone marrow or other tissues is a typical, yet initially often absent feature of the disease. Flow cytometric analysis of perforin expression and NKcell and CTL degranulation are helpful in supporting the rapid diagnosis of FHL, 7,[11][12][13] which then needs to be confirmed by genetic analysis. Unfortunately, since there are no characteristic prodromal signs, diagnosis in patients without other affected family members is usually not established before the first HLH episode.…”

A rare cause of thrombocyte dysfunction: Hermansky-Pudlak syndrome

“…None of these findings was present in our patient. In the literature, hemophagocytic lyphohistiocytosis has been reported in one patient (6). The AP3B1 gene is responsible of type 2.…”