Familial hemophagocytic lymphohistiocytosis in a neonate

Abstract

Rationale:Familial hemophagocytic lymphohistiocytosis (FHL) is a potentially fatal disease that rarely presents in the neonatal period. Timely diagnosis is a key challenge owing to the atypical clinical manifestations. Here, we describe a case of FHL type 3 with disease onset in the early neonatal period and review the relevant literature. Our findings may provide insights into the diagnosis and treatment of this rare disease.Patient concerns:A 6-day-old male neonate presented with fever, hepatosplenomegaly, cytopenia, hyperferritinemia, hypofibrinogenemia, hemophagocytosis, and hypertriglyceridemia.Diagnosis:Considering the clinical picture (prolonged fever, progressive hepatosplenomegaly, high triglycerides, low fibrinogen, and high ferritin), along with abnormal natural killer-cell activity, combining sequence analysis of genomic DNA results (compound heterozygous mutations of UNC13D), the patient was finally diagnosed with FHL type 3 (FHL3).Interventions:The patient was initially treated with HLH-1994 protocol and subsequently switched to an oral regimen of ruxolitinib due to incomplete remission of the disease.Outcomes:The trend of change in weekly cytokine levels, neutrophil counts, hemoglobin, and platelet counts indicated that the complete remission was not achieved after the treatment of HLH-1994 protocol. The platelet counts fluctuated within the normal range after oral administration of ruxolitinib. But soon after, the patient did not respond to treatment and eventually died of respiratory failure.Lesson:Timely diagnosis of FHL is challenging. This case report illustrates that thrombocytopenia can be the first clinical sign of FHL with neonatal onset. Genetic testing, detection of cytokines, and flow cytometry should be performed as soon as possible to confirm the diagnosis. Given the high morbidity and mortality of FHL, pediatricians should have a high suspicion index for this disease.

Case report: Optimized ruxolitinib-based therapy in an infant with familial hemophagocytic lymphohistiocytosis type 3

“…In the report, cytokine profiles of four patients with FHL were not shown ( 28 ). Cytokine profiles in our case and neonatal-onset FHL showed a non-responder pattern, suggesting that additional therapies are required for these cases ( 11 ). Except for one case without outcome information, 10 out of 12 cases were successfully managed by additional ruxolitinib administration ( Table 1 ).…”

“…FHL patients are predisposed to developing severe HLH even in utero or at birth, which can be fatal due to multiple organ failure, and often fail to survive until curative HCT (9)(10)(11). In the treatment strategy based on HLH-94/2004 protocols, HLH disease activity frequently recurs during steroid reduction and prolonged intervals of etoposide administration (12,13).…”

“…Ruxolitinib is known to inhibit JAK1, JAK2, and signal transducer and activator of transcription (STAT) 3 pathways, thereby reducing downstream signaling and cytokine production, including IL-6 and IFN-γ ( 20 – 22 ). Reports of the use of ruxolitinib as an immunomodulator for FHL have been published ( 11 , 23 – 29 ). However, the dose of ruxolitinib, combination of other therapies, and investigated cytokines were diversified.…”

Inborn Errors of Immunity With Fetal or Perinatal Clinical Manifestations

“…Primary or familial hemophagocytic lymphohistiocytosis (FHL) was one of the first IEI where intrauterine onset has been described in cases of non-immune hydrops fetalis, and, in more recent reports, hemophagocytic lymphohistiocytosis (HLH)associated gene mutations were identified (12,13,15,(40)(41)(42)(43). FLH is characterized by functional defects of cytotoxic T lymphocytes and NK cells, and associated with mutations in various genes, being PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5) the most frequently identified so far (3).…”

“…In reviewing 46 FHL patients who presented with initial symptoms in intrauterine or perinatal periods, hydrops fetalis was the most frequent manifestation (71%), being usually detected after 30 weeks of gestational age (GA), although there are cases described at the 24th week of GA, leading to stillbirths and prematurity with high mortality (12,13,15,(40)(41)(42)(43). Additionally, hepatosplenomegaly (50%), respiratory distress (27%), fever (27%), jaundice (23%), and petechiae (19%) were the most frequent initial symptoms at birth or perinatal age.…”