Synergistic defects of UNC13D and AP3B1 leading to adult hemophagocytic lymphohistiocytosis

Abstract

A 32-year-old man of non-consanguineous Chinese parentage, with high-grade fever, rash, joint pain, nausea, and vomiting, was diagnosed as adult-onset still's disease at his initial admission. Although prednisone had been taken, the patient presented with recurrent high-grade fever, rash, splenomegaly, hypertriglyceridemia, cryptogenic hepatitis, apparently elevated levels of serum ferritin(>20,000 μg/L), which met the proposed HLH diagnostic criteria, 2009. Sequence analysis of genomic DNA from the patient's peripheral blood demonstrated heterozygous for UNC13D mutation: c. 1232 G>A, and AP3B1 mutation: c. 1075 A>G, which were predicted to be pathogenic. Unfortunately, at the time, molecular confirmation results for HLH were obtained, and this patient had died from progressive HLH disease with multiple organ dysfunction syndrome caused by shock. FHL should be considered in the differential diagnosis of adults who present with adult-onset still's disease-like symptoms.

Hermansky–Pudlak syndrome: Mutation update

“…Next‐generation sequencing of different cohorts of subjects with primary immunodeficiency or hemophagocytic lymphohistiocytosis (HLH) reported least eight AP3B1 variants (Table S4) in a heterozygous state with or without a variant in another (synergistic) gene. These findings suggest that heterozygous AP3B1 variants may contribute to an immunologic phenotype (Chi et al, 2018; Gallo et al, 2016; Gao, Zhu, Huang, & Zhou, 2015; Miao et al, 2019; Mukda et al, 2017; Tesi et al, 2015; Xu et al, 2017). These variants have not been reported in HPS subjects but were included in this report because they may cause HPS when occurring in a homozygous or compound heterozygous state.…”

“…Individuals with HPS‐2 that present to an immunologist with (severe) immunodeficiency may escape diagnosis due to emphasis on their immunodeficiency, other mild manifestations (e.g., hypopigmentation, ocular findings, and bleeding diathesis) may be overlooked, there may be unfamiliarity with HPS‐2, and costs and lack of availability of AP3B1 genetic testing may provide obstacles to diagnosis. However, the recent significant number of heterozygous AP3B1 variants identified by next‐generation sequencing in cohorts with immunodeficiency disorders (Chi et al, 2018; Gallo et al, 2016; Gao et al, 2015; Miao et al, 2019; Mukda et al, 2017; Tesi et al, 2015; Xu et al, 2017) emphasizes the importance of including AP3B1 in immunodeficiency‐related gene panels and may result in the diagnosis of additional HPS‐2 cases.…”

“…Heterozygous HPS1 , HPS4 , and DTNBP1 variants were reported in familial (Stearman et al, 2019) or sporadic (Deng et al, 2018) pulmonary fibrosis cases (Tables 3, 6, and 9). Heterozygous AP3B1 variants have been reported in cases with primary immunodeficiency (Chi et al, 2018; Gallo et al, 2016) or HLH (Gao et al, 2015; Miao et al, 2019; Mukda et al, 2017; Tesi et al, 2015; Xu et al, 2017; Table 4), and heterozygous variants in AP3D1 , HPS3 , and HPS4 were reported in cases with autism spectrum disorder or schizophrenia (Fromer et al, 2014; Iossifov et al, 2014; Takata et al, 2018).…”

“…These findings suggest that heterozygous AP3B1 variants may contribute to an immunologic phenotype (Chi et al, 2018;Gallo et al, 2016;Gao, Zhu, Huang, & Zhou, 2015;Miao et al, 2019;Mukda et al, 2017;Tesi et al, 2015;Xu et al, 2017). These variants have not been reported in HPS subjects but were included in this report because they may cause HPS when occurring in a homozygous or compound heterozygous state.…”

FHLdb: A Comprehensive Database on the Molecular Basis of Familial Hemophagocytic Lymphohistiocytosis

“…In recent years and coinciding with the rapid evolution of NGS technology, the number of studies reporting new HLH-related variants has significantly increased (21,22), and these have elucidated that a proportion of sHLH patients with or without a functional defect harbor monoallelic variants in one of the FHL-related genes (23,24). In addition, novel types of inheritance have been proposed for HLH, including polygenic and dominant transmission models (25)(26)(27)(28).…”