Myeloproliferative/lymphoproliferative Neoplasms, Familial (Multiple Types), Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to multiple types of familial myeloproliferative/lymphoproliferative neoplasms (MPLPF) can be conferred by heterozygous mutation in the DDX41 gene (608170) on chromosome 5q35.3.

Description

Familial myeloproliferative/lymphoproliferative neoplasms is an autosomal dominant cancer predisposition syndrome characterized by adult-onset of hematologic malignancies mainly affecting the myeloid line. Most patients present with myelodysplastic syndrome (MDS; 614286) and/or acute myeloid leukemia (AML; 601626). Rare lymphoid malignancies, including lymphoma, can also occur. Some mutation carriers, even if unaffected by a hematologic malignancy, may have evidence of immune dysregulation disorders, including asthma, eczema, or juvenile arthritis. The disorder shows incomplete penetrance (summary by Lewinsohn et al., 2016). Patients may show a favorable response to treatment with lenalidomide (summary by Polprasert et al., 2015).

Clinical Features

Polprasert et al. (2015) reported 7 unrelated families in which at least 2 individuals had various myeloid neoplasms, including myelodysplastic syndrome (MDS), MDS evolving to AML, AML, refractory cytopenia with multilineage dysplasia (RCMD), and/or refractory anemia with excess blasts (RAEB). The disease showed protracted onset, with most patients presenting between 44 and 70 years of age. In 1 family, 2 clinically unaffected mutation carriers had slight monocytosis with the presence of immature monocytes on peripheral blood smear. Sixteen additional unrelated patients with a similar spectrum of disease, including 1 with chronic myelomonocytic leukemia (CMML), were also identified from a cohort of 1,034 patients with MDS/AML. Overall, DDX41 mutations and deletions occurred more frequently in patients with advanced MDS and in patients with AML, and were associated with inferior overall survival compared to patients without DDX41 genetic alterations.

Lewinsohn et al. (2016) reported 9 unrelated families with MDS and/or myeloid malignancies; several patients in 1 of the families had lymphoma. A tenth family (UoC family 127) was reported in the supplementary material. The mean age at onset of cytopenias followed by a diagnosis was 66 years (range, 50-80). Patients who developed MDS or AML presented most often with leukopenia or other cytopenias. In 3 families, mutation carriers had granulomatous or immune disorders presenting either before hematologic malignancies or in the absence of hematologic malignancies. These disorders included sarcoidosis, systemic lupus erythematosus, asthma, eczema, and juvenile arthritis. Rare individuals had other malignancies, including melanoma, although segregation analysis with the DDX41 mutation was inconclusive.

Clinical Management

Within a cohort of 111 patients with and without del(5q) treated with lenalidomide, Polprasert et al. (2015) found that patients with DDX41 mutations responded better to this treatment than those without DDX41 mutations, and those with decreased DDX41 mRNA levels responded the best to this treatment.

Inheritance

The transmission pattern of MPLPF in the families reported by Polprasert et al. (2015) was consistent with autosomal dominant inheritance and incomplete penetrance.

Molecular Genetics

In affected members of 7 unrelated families with MPLPF, Polprasert et al. (2015) identified a heterozygous germline mutation in the DDX41 gene (see, e.g., 608170.0001; 608170.0003-608170.0004). Most of the patients had a recurrent truncating mutation (Asp140fs; 608170.0001). About half of the patients also carried a somatic heterozygous missense mutation in the DDX41 gene (R525H; 608170.0002) on the other allele. This missense mutation was shown to be a hypomorphic allele. Subsequent targeted sequencing of the DDX41 gene in 1,034 patients with MDS/AML identified 16 with heterozygous germline and/or somatic DDX41 mutations. Two of these patients were diagnosed with chromosome 5q deletion syndrome (153550). Overall, DDX41 mutations and deletions occurred more frequently in patients with advanced MDS and in patients with AML, and were associated with inferior overall survival compared to patients without DDX41 genetic alterations. Knockdown of the DDX41 gene in human hematopoietic cells resulted in enhanced proliferation, enhanced colony formation, and increased sensitivity to growth factor stimuli compared to controls. Knockdown of DDX41 also impaired cell differentiation and increased resistance to apoptosis. Forced expression of the gene resulted in growth inhibition; these overall findings suggested that DDX41 has tumor suppressor functions. In vitro functional expression studies indicated that the R525H mutation interfered with the ability of DDX41 to interact with several major spliceosomal components, and DDX41-deficient cells showed multiple splicing defects, including exon skipping in the ZMYM2 gene (602221). Deletions of chromosome 5q involving the DDX41 gene were found in 6% of all cases and in 26% of the del(5q) cases; these resulted in decreased DDX41 mRNA levels, suggesting that some cases of 5q- syndrome may result from deletion of the DDX41 gene.

In affected individuals from 10 unrelated families with MPLPF, Lewinsohn et al. (2016) identified germline heterozygous mutations in the DDX41 gene (see, e.g., 608170.0001-608170.0002; 608170.0004-608170.0006). Lymphoma was diagnosed in affected members from only 1 family (CCB 25476) with a missense mutation (R164W; 608170.0006). In some cases, studies of patient cells showed deleterious effects of the mutation on protein expression, but functional studies of the variants were not performed. In the entire cohort, the majority of mutation carriers had normal peripheral blood counts well into adulthood, suggesting that haploinsufficiency of DDX41 is sufficient for normal baseline hematopoiesis. The authors stated that 9 of the families were ascertained from a cohort of 289 families with inherited hematologic malignancies who underwent whole-exome sequencing, panel-based next-generation sequencing, or targeted sequencing of the DDX41 gene; they thus accounted for about 3% of families.