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<p>Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is the commonest cause of familial hemophagocytic lymphohistiocytosis (FHLH). In this retrospective study, we analyzed 8 patients with a genetic diagnosis of FHL2 and then examined their clinicopathological and perforin flow cytometry results (&lt; 10% expression). The atypical clinical features in our cohort included tuberculosis, lymphoreticular malignancy, and necrotizing enterocolitis in 3 patients. A disease-causing variant was identified in the <i>PRF1</i> gene in all eight patients, comprising missense (n = 6), null (n = 1), and in-frame deletion (n = 1). Five patients had homozygous exon 3 disease-causing variants, two had homozygous exon 2 disease-causing variants, and one had compound heterozygous disease-causing variants in exon 2 and exon 3. After an extensive literature search, the mutations present in our North Indian cohort, including c.1284G &gt; A, c.895C &gt; T, c.853_855del, c.203G &gt; A, and c.757G &gt; A, are reported for the first time from India. Clinical and immunological phenotypes of c.1284G &gt; A and c.203G &gt; A variants have not been published in the literature. Hemophagocytosis was evident in bone marrow in 6 cases. Hyperferritinemia was absent in 3 cases, including c.148G &gt; A, c. 895C &gt; T, and c.1349C &gt; T homozygous variants. Neurological involvement, lymphoreticular malignancy, and necrotizing enterocolitis were seen in 2, 1, and 1 cases, respectively. Infections were present in 4 cases. Five children succumbed to HLH, and three are alive and planned for a hematopoietic stem cell transplant. FHL2 should be suspected in children with HLH irrespective of the age of onset, atypical clinical phenotype, family history, ferritin and fibrinogen levels, and infections. Flow cytometry-based perforin assay helps in rapid diagnosis of FHL2.</p>

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Clinicopathological and Immunogenetic Characterization in 8 Patients with Familial Hemophagocytic Lymphohistiocytosis Type 2: A Study from North India with Literature Review

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月19日

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  • Saniya Sharma,
  • Suprit Basu,
  • Taru Goyal,
  • Madhubala Sharma,
  • Prabal Barman,
  • Gurjit Kaur,
  • Jitendra K. Shandilya,
  • Pandiarajan Vignesh,
  • Rakesh Kumar Pilania,
  • Ankur Kumar Jindal,
  • Manpreet Dhaliwal,
  • Prateek Bhatia,
  • Sreejesh Sreedharanunni,
  • Pulkit Rastogi,
  • Nabhajit Mallik,
  • Prashant Sharma,
  • Anupriya Kaur,
  • Deepti Suri,
  • Amit Rawat,
  • Surjit Singh

摘要

Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is the commonest cause of familial hemophagocytic lymphohistiocytosis (FHLH). In this retrospective study, we analyzed 8 patients with a genetic diagnosis of FHL2 and then examined their clinicopathological and perforin flow cytometry results (< 10% expression). The atypical clinical features in our cohort included tuberculosis, lymphoreticular malignancy, and necrotizing enterocolitis in 3 patients. A disease-causing variant was identified in the PRF1 gene in all eight patients, comprising missense (n = 6), null (n = 1), and in-frame deletion (n = 1). Five patients had homozygous exon 3 disease-causing variants, two had homozygous exon 2 disease-causing variants, and one had compound heterozygous disease-causing variants in exon 2 and exon 3. After an extensive literature search, the mutations present in our North Indian cohort, including c.1284G > A, c.895C > T, c.853_855del, c.203G > A, and c.757G > A, are reported for the first time from India. Clinical and immunological phenotypes of c.1284G > A and c.203G > A variants have not been published in the literature. Hemophagocytosis was evident in bone marrow in 6 cases. Hyperferritinemia was absent in 3 cases, including c.148G > A, c. 895C > T, and c.1349C > T homozygous variants. Neurological involvement, lymphoreticular malignancy, and necrotizing enterocolitis were seen in 2, 1, and 1 cases, respectively. Infections were present in 4 cases. Five children succumbed to HLH, and three are alive and planned for a hematopoietic stem cell transplant. FHL2 should be suspected in children with HLH irrespective of the age of onset, atypical clinical phenotype, family history, ferritin and fibrinogen levels, and infections. Flow cytometry-based perforin assay helps in rapid diagnosis of FHL2.