Familial Hemophagocytic Lymphohistiocytosis Type 2 in a Korean Infant With Compound Heterozygous <i>PRF1</i> Defects Involving a <i>PRF1</i> Mutation, c.1091T&gt;G

Kim, Min Sun; Cho, Young Uk; Jang, Seongsoo; Seo, Eul Ju; Im, Ho Joon; Park, Chan Jeoung

doi:10.3343/alm.2017.37.2.162

Cited by 5 publications

(5 citation statements)

References 10 publications

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“…A limited fraction of case reports can be found in the literature, in which the presence of compound heterozygosity of two variants in the PRF1 gene also led to the development of severe HLH. However, the reported genetic constellations differ from the constellation reported here [ 28 , 32 ].…”

Section: Discussioncontrasting

confidence: 94%

Late Onset of Primary Hemophagocytic Lymphohistiocytosis (HLH) with a Novel Constellation of Compound Heterozygosity Involving Two Missense Variants in the PRF1 Gene

Stadermann,

Haar,

Riecke

et al. 2024

IJMS

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Hemophagocytic lymphohistiocytosis (HLH) is a rare but in most cases life-threatening immune-mediated disease of the hematopoietic system frequently associated with hematologic neoplasms. Here, we report on a case in which we detected a novel constellation of two missense variants affecting the PRF1 gene, leading to de novo primary HLH. Diagnostics included a comprehensive clinical work-up and standard methods of hematopathology as well as extended molecular genomics based on polymerase chain reaction (PCR) reactions and the calculation of three-dimensional molecule reconstructions of PRF1. Subsequently, a comprehensive review of the literature was performed, which showed that this compound heterozygosity has not been previously described. The patient was a 20-year-old female. Molecular diagnostics revealed two heterozygous missense variants in the PRF1 gene (A91V and R104C) on exon 2. Apart from the finding of two inconclusive genetic variants, all clinical criteria defined by the HLH study group of Histiocyte Society were met at initial presentation. The final diagnosis was made in cooperation with the Consortium of German HLH—reference centers. Here, chemotherapy did not lead to sufficient sustained disease control. Therefore, the decision for allogenic hematopoietic stem cell transplantation (alloHSCT) was made. Hitherto, the duration of response was 6 months. Due to severe and unmanageable hepatic graft-versus-host disease (GvHD), the patient died. We report on a novel constellation of a compound heterozygosity containing two missense variants on exon 2 of the PRF1 gene. To the authors’ best knowledge, this is the first presentation of a primary HLH case harboring this genomic constellation with late-onset clinical manifestation.

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Section: Discussioncontrasting

confidence: 94%

Late Onset of Primary Hemophagocytic Lymphohistiocytosis (HLH) with a Novel Constellation of Compound Heterozygosity Involving Two Missense Variants in the PRF1 Gene

Stadermann,

Haar,

Riecke

et al. 2024

IJMS

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“…The above inducing factors have been excluded. Combined with the literature about c.65delC mutations, it is found that FHL2 with this kind of mutation occurs in both infants and adults[ 1 , 2 , 10 ]. We propose that the mutation type of the pathogenic gene is not a single determinant of the age of onset.…”

Section: Discussionmentioning

confidence: 94%

“…In this patient, the two mutations of PRF1 are both located in the MACPF/CDC domain and recorded in 460 single-nucleotide variants of PRF1 reported by Willenbring et al [ 5 ]. The c.65delC mutation has been reported in both China and South Korea[ 1 , 2 , 10 ]. Except for only one case of FHL2 caused by single allele heterozygous mutation[ 1 ], all others were caused by a compound heterozygous mutation.…”

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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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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“…The c.148G > A [V50M] missense mutation is conserved in human, mouse and rat (Lowin et al, 1995). The c.65delC mutation [p.P22Rfs*2] was previously reported in two patients from Korea and one from Hong Kong in a compound heterozygous manner (Chiang et al, 2014;Kim et al, 2014;Kim et al, 2017). Two of the patients (one from Korea and one from Hong Kong) were diagnosed with CNS involved FHL2 (Chiang et al, 2014;Kim et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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

Feng

Yang

et al. 2020

Front. Genet.

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Familial Hemophagocytic Lymphohistiocytosis Type 2 in a Korean Infant With Compound Heterozygous PRF1 Defects Involving a PRF1 Mutation, c.1091T>G

Cited by 5 publications

References 10 publications

Late Onset of Primary Hemophagocytic Lymphohistiocytosis (HLH) with a Novel Constellation of Compound Heterozygosity Involving Two Missense Variants in the PRF1 Gene

Late Onset of Primary Hemophagocytic Lymphohistiocytosis (HLH) with a Novel Constellation of Compound Heterozygosity Involving Two Missense Variants in the PRF1 Gene

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

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

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