Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare neuroinflammatory syndrome most commonly described in middle-aged adults, though it can occur in children. Its etiology remains unknown, and diagnosis is challenging due to lack of a specific biomarker. Patients commonly present with gait ataxia, speech disturbances, cognitive impairment, diplopia, and demonstrate a marked response to steroid therapy. Characteristic MRI findings include pontine and cerebellar nodules with gadolinium enhancement.

Here, we present two patients initially diagnosed with CLIPPERS, ultimately found to have familial hemophagocytic lymphohistiocytosis (HLH) from biallelic mutations in RAB27A and PRF1, respectively.

A previously healthy 6-year-old female presented with decreased speech, ataxia, and headache following a viral infection. Imaging demonstrated acute cerebellitis, ventriculomegaly, and acute hydrocephalus. She initially improved with high-dose steroids but relapsed after tapering. Despite improvement on tocilizumab, she continued to relapse. Brain biopsy was consistent with CLIPPERS; however, genetic evaluation revealed biallelic pathogenic mutations in RAB27A, consistent with Griscelli Syndrome type 2 and HLH. She responded well to intrathecal chemotherapy and is planned for a hemopoietic stem cell transplant.

Similarly, a 9-year-old male presented with slurred speech, ataxia, and ophthalmoplegia with imaging and pathology suggestive of CLIPPERS. His course was complicated by years of relapsing disease. Ultimately, genetic testing revealed biallelic PRF1 mutations, confirming familial HLH. He underwent several treatments, including intrathecal chemotherapy, but ultimately died from progressive neurologic decline.

Although both patients had clinical and radiological findings consistent with CLIPPERS, and lacked prior symptoms of systemic HLH, their diagnoses were revised after genetic evaluation. These cases highlight the importance of considering familial HLH in patients with CLIPPERS-like presentations.  Early genetic testing is critical, as HLH-directed therapy, including chemotherapy and hematopoietic stem cell transplantation, may be lifesaving.