Hemophagocytic Lymphohistiocytosis Gene Mutations in Adult Patients Presenting With CLIPPERS-Like Syndrome

Abstract

ObjectiveTo determine whether adult cases of Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) may be related to familial hemophagocytic lymphohistiocytosis (HLH) causes, we have screened patients with adult-onset CLIPPERS for mutations in primary HLH-associated genes.MethodsIn our cohort of 36 patients fulfilling the criteria for probable or definite CLIPPERS according to the CLIPPERS-2017 criteria, we conducted a first study on 12 patients who consented to genetic testing. In these 12 patients, systemic HLH criteria were searched, and genetic analysis of 8 genes involved in primary HLH was performed.ResultsFour definite and 8 probable CLIPPERS were enrolled (n = 12). Mutations involved in HLH were identified in 2 definite and 2 probable CLIPPERS (4/12). Three of them had biallelic PRF1 mutations with reduced perforin expression in natural killer cells. The remaining patient had biallelic UNC13D mutations with cytotoxic lymphocyte impaired degranulation. None of the mutated patients reached the criteria for systemic HLH. During follow-up, 3 of them displayed atypical findings for CLIPPERS, including emergence of systemic non-Hodgkin lymphoma (1/3) and confluent gadolinium-enhancing lesions on brain MRI (3/3).ConclusionsIn our patients presenting with adult-onset CLIPPERS, one-third have HLH gene mutations. This genetic treatable condition should be searched in patients with CLIPPERS, especially in those presenting with atypical findings.

Isolated central nervous system familial hemophagocytic lymphohistiocytosis (fHLH) presenting as a mimic of demyelination in children

“…In this case series, we demonstrate that fHLH can present as an atypical neuroinflammatory condition, with striking neuroimaging findings, raised CSF protein and variable response to steroids early on in presentation or during disease course. This is consistent with two other cases series in children 6 and adults 7 . The mechanisms for how HLH causes CNS restricted neuroinflammation are not fully understood but may be related to functional defects in T lymphocyte and NK cell cytotoxicity causing impaired antigen clearance which occurs in systemic HLH 8 .…”

“…This is consistent with two other cases series in children 2 and adults. 6 The mechanisms for how HLH causes CNS restricted neuroinflammation are not fully understood but may be related to functional defects in T lymphocyte and NK cell cytotoxicity causing impaired antigen clearance which occurs in systemic HLH. 7…”

“…This is consistent with two other cases series in children 2 and adults. 6 The mechanisms for how HLH causes CNS restricted neuroinflammation are not fully understood but may be related to functional defects in T lymphocyte and NK cell cytotoxicity causing impaired antigen clearance which occurs in systemic HLH. 7 In all our cases, there were no signs of systemic inflammation on initial presentation, but in six cases, inflammation meeting the criteria for systemic HLH became apparent over time.…”

MRI Patterns in Pediatric CNS Hemophagocytic Lymphohistiocytosis

“…Five similar children with imaging showing cerebellar swelling at the onset of primary HLH have been described previously (Table 3). 3,[26][27][28][29] Cerebellitis preceded systemic involvement or was followed by CNS-restricted disease in 4 cases. An unfamiliarity with this pattern led to diagnostic delays, and these children subsequently developed multifocal white matter lesions on follow-up.…”

“…A CLIPPERS-like pattern has been reported in adult-onset HLH with hypomorphic missense mutations with residual protein expression. 28 This association, thus, may possibly be limited to young children, and there may be other age-related factors, extrinsic triggers, and susceptibility loci influencing MR imaging pattern presentations.…”