Elsevier

Leukemia Research

Volume 67, April 2018, Pages 39-44
Leukemia Research

Research paper
Pulmonary Langerhans cell histiocytosis, acute myeloid leukemia, and myelofibrosis in a large family and review of the literature

https://doi.org/10.1016/j.leukres.2018.01.011Get rights and content

Highlights

  • Familial associations of LCH, AML, and MF were reported primarily in siblings.

  • Recent evidence suggests that LCH may arise from myeloid progenitor cells.

  • This family has LCH, AML, and MF in multiple generations, with anticipation.

  • This study supports a common genetic etiology for LCH, AML and MF.

  • Molecular studies may discover the precise genetic basis for these entities.

Abstract

Background

There is mounting evidence that Langerhans cell histiocytosis (LCH) and acute myeloid leukemia (AML) are hematopoietic neoplasms that arise from the same myeloid precursor cell. In addition, studies suggest a relationship between LCH and primary idiopathic myelofibrosis (MF). Furthermore familial LCH, AML, and MF have each been reported.

Methods

We examined more than 750 pedigrees of familial hematologic malignancies for evidence of familial LCH, AML, and/or MF and identified one family with all three neoplasms, which is presented here.

Findings

In four generations of this large family there are five cases of AML in three generations, two cases of LCH in two generations and three cases of MF in two generations. Anticipation of −18 and −6 years was present in the patients with MF, and −8 years in the patients with LCH. Anticipation was also identified between one AML patient pair in generations III and IV (−18 years) and three patients with AML in generations II, III, and IV (−5 years and −10 years).

Interpretation

This is the first report of familial LCH, AML, and MF in one family. The pedigree suggests a common basis for these entities, which is further suggested by the presence of anticipation in the pedigree.

Introduction

Eosinophilic granuloma (now termed Langerhans cell histiocytosis) has been recognized as a distinct entity since described by Lichtenstein and Jaffe in 1940 [1]. Subsequently it was shown to be a histiocytic reticulosis related to Letterer-Siwe disease and Hand-Schüller-Christian disease [2]. Clinical aspects of primary pulmonary Langerhans cell histiocytosis (LCH) were well described by Friedman, et al. [3]. Here we report a large family with multiple cases of LCH of the lung, primary myelofibrosis and acute myeloid leukemia (AML). It is possible that there is a common genetic aberration in this family that caused or facilitated the development of these disorders. The recent discovery that LCH may be of hematopoietic origin makes the family reported here especially interesting [[4], [5]].

Section snippets

Materials and methods − new family

We present here a large family (Table 1, Fig. 1) with two cases of LCH of the lung, three cases of primary myelofibrosis, five cases of AML, and nine cases of other hematologic and non-hematologic malignancies, including one each of myelodysplastic syndrome and chronic myelocytic leukemia (CML). Although LCH was not biopsy proven in patient 6, he had classic radiographic findings of pulmonary LCH. In such cases biopsy is not necessary to establish the diagnosis [6]. The subjects in this family

Literature review

Familial LCH has been previously uncommonly reported in infants and children [[7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]] (Table 2) and even more rarely in adults [[20], [21], [22], [23], [24], [25]] (Table 3). Most pediatric familial cases have been male identical twins (Table 2) and most have had disseminated disease. Most multigenerational pairs have been concordant for sex, of adolescent or adult age and have had localized disease (Table 3).

Familial

Discussion

Lichtenstein et al. [54] coined the term, histiocytosis X to include Letterer-Siwe disease, Hand-Schüler-Christian disease and eosinophilic granuloma in 1953. The Histiocyte Society 34 years later suggested that the designation be changed to LCH [55], the term in current use.

Familial LCH has been well documented in the literature and suggests that a genetic mutation or other alteration may be responsible for the predisposition for the disease in such families. The multigenerational involvement

Role of the funding sources

The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit the paper for publication.

Contributors

MB, JPD, PHW identified the family of interest from the Familial Hematologic Malignancy Registry of the Cancer Research Foundation (Western Investigational Review Board approval 1164273). MB and JPD constructed case studies and Table 1. MB, JPD, PHW conducted the literature review. PHW wrote the initial draft and constructed Table 2, Table 3, Table 4, Table 5. MB and JPD constructed the pedigree (Fig. 1). All authors read and approved the final manuscript.

Declaration of interests

All authors declare no competing interests.

Acknowledgements

This study was funded in part by the Cancer Research Foundation of New York (thecrf.org) and a grant from Children’s Leukemia Research Association.

We thank Maria Thomas for translation of French References.

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