Genetic Features of Late Onset Primary Hemophagocytic Lymphohistiocytosis in Adolescence or Adulthood

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of uncontrolled immune activation leading to extreme inflammation. Primary HLH was once believed to be a disease that occurred only in infancy or young children, and was rarely diagnosed in adults. It is now understood that patients can develop primary HLH in their adolescence or adulthood. This study included 252 adolescent and adult patients with a clinical diagnosis of HLH from 35 general medical institutions across mainland China. All exons and 50 bp of flanking intronic sequence of six HLH-related genes (PRF1, UNC13D, STX11, STXBP2, SH2D1A, and BIRC4) were sequenced in these patients. We identified mutations in 18/252 (7.1%) of the patients, with changes in PRF1 being most common. Late-onset HLH often features viral infection and other predisposing factors. We conclude that late-onset primary HLH is not as rare as previously thought. Older patients should not be delayed to receive HLH-related genes testing when they are suspected with HLH.

A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis

“…An extensive infectious work-up was unrevealing with notably negative or normal evaluations for hepatitis A/B/C, HIV-1, EBV, CMV, Ehrlichia chaffeensis , and enterovirus. Her ANA test was negative, but her serum complement levels were low [C3 - 20 mg/dL (51–95), C4 - 3 mg/dL (8–44)], a feature of MAS (35). The bone marrow biopsy specimen was essentially normal except that CD163 staining revealed increased numbers of activated macrophages.…”

“…Those lacking family history or known genetic mutations were previously classified as having acquired, reactive, or sHLH (41). However, recent reports have detailed many later-onset sHLH and MAS patients found to have heterozygous mutations of the same fHLH causing genes (17–20, 22–24, 42–44), although without any supporting functional or mechanistic analyses of the effects of these heterozygous mutants, except for a few studies (17, 24, 42). …”

Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities

“…Rather, 'milder' missense mutations are detected Wang et al, 2014;Tesi et al, 2015a;Cetica et al, 2016), causing partial impairment of protein function or decreased protein production. Additionally, mutations may be found outside of the coding sequence, in evolutionary conserved noncoding regions, including splice-site mutations, resulting in transcript defects, and mutations in intronic transcription regulatory regions, disrupting transcription factor binding (Pagel et al, 2012;Entesarian et al, 2013;Meeths et al, 2014;Qian et al, 2014;Zhang et al, 2014b).…”

“…Evidence is currently accumulating for genetic overlap between both. In some patients with classical 'secondary' HLH, monoallelic mutations or polymorphisms have been detected in genes typically implicated in primary HLH (Table II) (Kaufman et al, 2014;Wang et al, 2014;Zhang et al, 2014a,b). Some of these polymorphisms are relatively frequent in the general population (up to 9% minor allele frequency for PRF1 A91V), while several base changes, present in non-conserved gene regions, are predicted in silico to be benign.…”

“…Both subtypes comprise heterozygous monogenic, bigenic or polygenic subgroups (Kaufman et al, 2014;de Saint Basile et al, 2015). Nonetheless, patients carrying typical primary HLH-linked mutations or polymorphisms account for only a minor percentage of secondary HLH, approximately 7-18% in the largest cohorts (Zhang et al, , 2014aWang et al, 2014;Cetica et al, 2016), signifying the existence of other predisposing factors in the majority of secondary HLH patients.…”