Our finding expands the spectrum of SIGMAR1 mutations causing recessive dHMN and indicates that this disorder is pan-ethnic. SIGMAR1 mutation should be included in the diagnostic panel of a dHMN, especially if there are co-existing pyramidal signs and autosomal recessive inheritance.
Charcot-Marie-Tooth neuropathy type 4B1 (CMT4B1) disease is a rare subtype of CMT4 with reported association of facial weakness, vocal cord paresis, chest deformities, and claw hands. We report the unusual occurrence of optic neuritis and cervical cord schwannoma in a male individual with confirmed CMT4B1 disease. Sequencing of the MTMR2 gene revealed a novel nonsense homozygous mutation c.1768C>T (p.Gln590*). The mutation was identified in affected relatives of the proband and a second, apparently unrelated, family. The rare association of optic neuritis or schwannoma with genetically confirmed CMT1A has been individually observed, but never with recessive CMT. To the best of our knowledge, the occurrence of optic neuritis and cervical cord schwannoma in the same patient has never been reported with any form of CMT including CMT4B1. In similar cases, we recommend immediate medical attention to rule out the possibility of schwannomas in patients with all demyelinating CMT subtypes in case of the development of focal neurological signs or acute worsening of clinical status.
The RUNX1 gene encodes the DNA-binding subunit of the heterodimeric transcription factor core binding factor (CBF) and is involved in the regulation of several genes important for hematopoiesis. RUNX1 is frequently rearranged by chromosomal translocations in a spectrum of hematologic malignancies, generating a RUNX1 fusion gene. Some of these RUNX1 fusion genes have been shown to be important in leukemogenesis, such as the ETV6/RUNX1 fusion in B-lineage acute lymphoblastic leukemia and the RUNX1/RUNX1T1 fusion in M2 acute myeloid leukemia (AML). We here describe the first case of adult AML with the t(7;21)(p22;q22) cryptic translocation. Morphologic analysis showed an AML without maturation (AML M1). The karyotype was 46, XY, del(5)(q22q33),?del(21)(q22) in twenty metaphases and analysis by spectral karyotyping (SKY) revealed a t(7;21). The translocation breakpoints at bands 21q22 and 7p22 were studied using bacterial artificial chromosomes (BACs) and showed RUNX1 and USP42 rearrangements. An in-frame fusion between RUNX1 exon 7 and USP42 exon 3 was confirmed by RT-PCR and sequencing. The RUNX1/USP42 fusion includes both the DNA binding RUNT domain of RUNX1 and the catalytic region of USP42. The RUNX1/USP42 fusion gene has recently been reported in one case of pediatric AML-M0 with normal karyotype at diagnosis (Paulsson et al., Leukemia2006;20:224). A complex karyotype including a deletion of the long arm of chromosome 5 was found at relapse in this case. Interestingly, blast cells in our t(7;21) positive leukemia share similar features with the previously published case. By flow cytometry, leukemic cells were positive for HLA-DR, CD34, CD33, CD13 markers and aberrantly expressed CD7 and CD56 without B-lineage markers. We next analyzed samples of CD7 and CD56 positive AMLs with different karyotypes (normal and complex) by FISH using probes to detect the RUNX1/USP42 fusion gene. The USP42 gene encodes a cysteine protease involved in the ubiquitin pathway as a deubiquitinating enzyme. Ubiquitin-specific proteases (USPs) are a large group of enzymes with highly conserved amino acid sequences that form the catalytic region. Some USPs have been shown to be involved in the stabilization of proteins, such as p53, and in the regulation of gene silencing. USP42 is part of a novel class of genes involved in the pathogenesis of leukemia and its role in hematologic cancers remains to be studied. To elucidate the possible implication of USP42 in hematologic malignancies, the expression of USP42 was also investigated by real-time PCR in our case with t(7;21) and in a series of acute leukemias.
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