Neurologic Manifestations as Initial Clinical Presentation of Familial Hemophagocytic Lymphohistiocytosis Type2 Due to PRF1 Mutation in Chinese Pediatric Patients

Feng, Weixing; Yang, Xinying; Li, Jiuwei; Gong, Shuai; Wu, Yun; Zhang, Weihua; Tong, Haizhou; Zhuo, X W; Ding, Changhong; Fang, Fang

doi:10.3389/fgene.2020.00126

Cited by 16 publications

(15 citation statements)

References 24 publications

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“…According to our literature review, the delayed onset of FHL2 may be related to the mutation type[ 11 - 13 ], triggering factors[ 14 - 15 ], and pathogenic variation pattern of PRF1 [ 16 - 18 ]. Additionally, the temperature sensitivity of some PRF1 mutations can also explain this[ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…The onset age of patients with two destructive mutations (frameshift mutation or nonsense mutation) is significantly earlier than that of patients with a destructive mutation and a missense mutation. Using whole-exome sequencing (WES), Feng et al [ 13 ] advanced that FHL2 patients with compound heterozygous mutations of PRF1 have delayed onset; a possible explanation for this phenomenon is that these patients carry a heterozygous missense mutation, which encodes part of the PRF1 activity. Ueda et al [ 20 ] reported an 11-year-old late-onset FHL2 with compound heterozygous missense mutations of PRF1 .…”

Section: Discussionmentioning

confidence: 99%

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Adult onset type 2 familial hemophagocytic lymphohistiocytosis with PRF1 c.65delC/c.163C>T compound heterozygous mutations: A case report

Liu

Nie²,

Chen

et al. 2021

WJCC

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BACKGROUND Familial hemophagocytic lymphohistiocytosis (FHL) is a primary immunodefici-ency disease caused by gene defects. The onset of FHL in adolescents and adults may lead clinicians to ignore or even misdiagnose the disease. To the best of our knowledge, this is the first report to detail the clinical features of type 2 FHL (FHL2) with compound heterozygous perforin ( PRF1 ) defects involving the c.163C>T mutation, in addition to correlation analysis and a literature review. CASE SUMMARY We report a case of a 27-year-old male patient with FHL2, who was admitted with a persistent fever and pancytopenia. Through next-generation sequencing technology of hemophagocytic lymphohistiocytosis (HLH)-related genes, we found compound heterozygous mutations of PRF1 : c.65delC (p.Pro22Argfs*29) (frameshift mutation, paternal) and c.163C>T (p.Arg55Cys) (missense mutation, maternal). Although he did not receive hematopoietic stem cell transplantation, the patient achieved complete remission after receiving HLH-2004 treatment protocol. To date, the patient has stopped taking drugs for 15 mo, is in a stable condition, and is under follow-up observation. CONCLUSION The delayed onset of FHL2 may be related to the PRF1 mutation type, pathogenic variation pattern, triggering factors, and the temperature sensitivity of some PRF1 mutations. For individual, the detailed reason for the delay in the onset of FHL warrants further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adult onset type 2 familial hemophagocytic lymphohistiocytosis with PRF1 c.65delC/c.163C>T compound heterozygous mutations: A case report

Liu

Nie²,

Chen

et al. 2021

WJCC

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“…Patients with FHL may also present with neurological symptoms, including seizures, facial paralysis, gait instability, or even coma. It is worth noting that FHL is more susceptible to neurologic involvement than the non-familial HLH[ 11 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Five subtypes of FHL have been identified. Except for FHL1, which has no precise gene location being identified, each subtype is caused by its respective gene mutation such as PRF1, UNC13D, STX11 , and STXBP2 [ 11 ]. Mutations involving PRF1 and UNC13D are more pathogenic than STX11 and STXBP2 , as shown in studies involving Italian, Turkish, and Korean cohorts[ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Familial hemophagocytic lymphohistiocytosis type 2 in a female Chinese neonate: A case report and review of the literature

Bi¹,

Jiang²,

Dai³

et al. 2021

WJCC

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BACKGROUND Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is a rare genetic disorder presenting with fever, hepatosplenomegaly, and pancytopenia secondary to perforin-1 (PRF1) mutation. FLH2 has been described in Chinese but usually presents after 1 year old. We describe a female Chinese neonate with FHL2 secondary to compound heterozygous PRF1 mutation with symptom onset before 1 mo old. We review Chinese FHL2 patients in the literature for comparison. CASE SUMMARY A 15-d-old female neonate was referred to our hospital for persistent fever and thrombocytopenia with diffuse petechiae. She was born to a G5P3 mother at 39 wk and 4 d via cesarean section secondary to breech presentation. No resuscitation was required at birth. She was described to be very sleepy with poor appetite since birth. She developed a fever up to 39.5°C at 7 d of life. Leukocytosis, anemia, and thrombocytopenia were detected at a local medical facility CONCLUSION A literature review identified 75 Chinese FHL2 patients, with only five presenting in the first year of life. Missense and frameshift mutations are the most common PRF1 mutations in Chinese, with 24.8% having c.1349C>T followed by 11.6% having c.65delC. The c.658G>C mutation has only been reported once in the literature and our case suggests it can be pathogenic, at least in the presence of another pathogenic mutation such as c.1066C>T.

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“…MRI abnormalities have been reported in FHL due to PRF1 variants even in the absence of neurological symptoms (184). Therefore, CNS-HLH is frequently initially diagnosed as acute demyelinating encephalomyelitis (ADEM), CNS vasculitis, meningitis, leukodystrophy, or MS (38,(185)(186)(187)(188). The mean time from onset of symptoms of CNS-HLH to confirmed molecular diagnosis is more than two years in published cases and it is recognized that a fully developed HLH disease can arise several years after onset of CNS-HLH (33).…”

Section: Familial Hemophagocytic Lymphohistiocytosismentioning

confidence: 99%

Neuroinflammation Associated With Inborn Errors of Immunity

Lindahl

Bryceson

2022

Front. Immunol.

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The advent of high-throughput sequencing has facilitated genotype-phenotype correlations in congenital diseases. This has provided molecular diagnosis and benefited patient management but has also revealed substantial phenotypic heterogeneity. Although distinct neuroinflammatory diseases are scarce among the several thousands of established congenital diseases, elements of neuroinflammation are increasingly recognized in a substantial proportion of inborn errors of immunity, where it may even dominate the clinical picture at initial presentation. Although each disease entity is rare, they collectively can constitute a significant proportion of neuropediatric patients in tertiary care and may occasionally also explain adult neurology patients. We focus this review on the signs and symptoms of neuroinflammation that have been reported in association with established pathogenic variants in immune genes and suggest the following subdivision based on proposed underlying mechanisms: autoinflammatory disorders, tolerance defects, and immunodeficiency disorders. The large group of autoinflammatory disorders is further subdivided into IL-1β-mediated disorders, NF-κB dysregulation, type I interferonopathies, and hemophagocytic syndromes. We delineate emerging pathogenic themes underlying neuroinflammation in monogenic diseases and describe the breadth of the clinical spectrum to support decisions to screen for a genetic diagnosis and encourage further research on a neglected phenomenon.

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Neurologic Manifestations as Initial Clinical Presentation of Familial Hemophagocytic Lymphohistiocytosis Type2 Due to PRF1 Mutation in Chinese Pediatric Patients

Cited by 16 publications

References 24 publications

Adult onset type 2 familial hemophagocytic lymphohistiocytosis with PRF1 c.65delC/c.163C>T compound heterozygous mutations: A case report

Adult onset type 2 familial hemophagocytic lymphohistiocytosis with PRF1 c.65delC/c.163C>T compound heterozygous mutations: A case report

Familial hemophagocytic lymphohistiocytosis type 2 in a female Chinese neonate: A case report and review of the literature

Neuroinflammation Associated With Inborn Errors of Immunity

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