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

The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2

“…2,[5][6][7][11][12][13][14] As for other subtypes of HPS, affected patients have a diathesis toward bleeding as the result of a platelet storage pool deficiency 34 and a risk of lung fibrosis as the result of aberrant repair mechanisms of the lung caused by lysosomal mistrafficking. 21 In addition, however, patients with HPS2 have significant immunological problems, manifesting mainly as chronic neutropenia and a susceptibility to infections.…”

“…Two further patients had spontaneously resolving episodes of fever and cytopenia in association with varicella and CMV infections that did not fulfill the diagnostic criteria but may have represented incomplete manifestations of HLH. 6,7 Of the 5 reported deaths in HPS2 patients, 1 was from HLH, 2 from pneumonia in the context of lung fibrosis and 2 after accidents. In 4 patients without any HLH-related symptoms, asymptomatic seroconversion to Epstein-Barr virus, a known strong trigger for HLH, was documented.…”

“…5 This case, however, is the only one of severe HLH among 12 published patients with HPS2. 2,[5][6][7][11][12][13][14] Because this patient also carried a heterozygous RAB27A mutation (causing GS2, if homozygous), it remains unclear whether HPS2 per se confers a risk for HLH or if the HLH observed in that patient was attributable to this additional mutation. Transient episodes of HLH were thereafter described in another patient with HPS2, 6 and 1 additional patient had recurrent inflammatory episodes that did not fulfill all diagnostic criteria for HLH.…”

“…3 Immunological studies have shown that AP-3 deficiency leads to a defect in cytotoxicity of natural killer (NK) cells and cytotoxic T cells (CTL) as the result of impaired biogenesis and degranulation of perforin-containing lytic granules. [4][5][6][7] Defective cytotoxicity caused by impaired degranulation also is observed in other disorders of lysosomal trafficking, such as Chediak-Higashi syndrome (CHS) and Griscelli syndrome type 2 (GS2), which are associated with albinism and in familial hemophagocytic lymphohistiocytosis (FHL) types 3-5. 8,9 All of these diseases confer a high risk of developing hemophagocytic lymphohistiocytosis (HLH), a severe disorder of immune homeostasis that leads to a life-threatening hyperinflammatory disease.…”

Impairment of dendritic cell functions in patients with adaptor protein-3 complex deficiency

“…7,8 Neutrophils are also involved, but neutropenia that is observed in all HPS2 patients is usually responsive to granulocyte colony-stimulating factor (CSF) treatment, suggesting that the neutrophil abnormalities do not account for the susceptibility to infections. 9 There is evidence that AP-3 is involved in toll-like receptor (TLR) signaling and major histocompatibility complex functions of murine dendritic cells (DCs). 10 In addition, AP-3 is essential for TLR7-and TLR9-dependent secretion of type I interferon (IFN) by plasmacytoid DCs (pDCs).…”