Duchenne Muscular Dystrophy and Concomitant Metastatic Alveolar Rhabdomyosarcoma

Abstract

A case of juvenile myelomonocytic leukemia (JMML, previously referred to as JCML) in a neonate with Noonan syndrome (NS) is described. The boy presented with bilateral congenital hydrothoraces, nonimmune hydrops, dysmorphic facies, persistent thrombocytopenia, and leukocytosis. The diagnosis of JMML was made on bone marrow cell culture studies. Review of the literature reveals an unusual preponderance of hematologic malignancies, in particular JMML, among patients with NS. Of 40 NS patients admitted to the authors' institution during a 10-year period, there were 4 (10%) with evidence of a monocytic proliferation, which resolved spontaneously. The authors postulate that patients with NS may have an increased incidence of myeloproliferative disorders, which in most cases appears to be benign but may be preleukemic or even lethal.

Mice Lacking Dystrophin or α Sarcoglycan Spontaneously Develop Embryonal Rhabdomyosarcoma with Cancer-Associated p53 Mutations and Alternatively Spliced or Mutant Mdm2 Transcripts

“…While there are case reports of RMS occurring in DMD patients, 90,91 the incidence does not appear to be above what one might expect in the general population for a combination of a rare X-linked neuromuscular disease and a rare childhood cancer. Again, such a conclusion is difficult to extrapolate to the experiments shown here because there are fundamental differences between mdx mice and DMD patients that could explain such a disparity.…”

Genetics and Variation in Phenotype in Noonan Syndrome

“…Noonan syndrome has been associated with myeloid disorders [10, 11, 12]. A 218C→T mutation was found by Tartaglia et al [7]in four out of five Noonan syndrome patients with JMML.…”

FOXO1–FGFR1 fusion and amplification in a solid variant of alveolar rhabdomyosarcoma

“…33 Interestingly, DMD gene and other members in the dystrophinassociated glycoprotein (DAG) complex have also been studied in rhabdomyosarcoma but no clear interpretation is available at present, yet it is interesting to note that knockout mice with dystrophin or a-sarcoglycan deficiency spontaneously develop alveolar rhabdomyosarcoma or embryonal rhabdomyosarcoma in aged individuals; however, we could find only two Duchenne muscular dystrophy patients with rhabdomyosarcoma reported in the literature, which may be a coincidence. 16,17 Solid variant of alveolar rhabdomyosarcoma is rare and sometimes mimics other malignancies. 34 The 12 cases in the literature since 1994 including the current one are summarized in Supplementary Table 1.…”

“…4 Chromosome rearrangements not involving the FOXO1 locus have also been described in both alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma. 5 In embryonal rhabdomyosarcoma, gains of all or portions of chromosomes 2,7,8,11,12,13,17,19, and 20, with a particularly highlevel gain of chromosome 8 material are consistently observed, [6][7][8] and loss of heterozygosity (LOH) on the short arm of chromosome 11 (11p15.5) is frequently detected, suggesting that imprinting might be involved. 9 In both alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma, amplification of genes such as MYCN, MDM2, CDK4 and IFG-R1 are often observed.…”

“…[10][11][12][13][14] Despite the usually sporadic occurrence of rhabdomyosarcoma, it has also been reported in various congenital disorders, including cancer predisposition syndromes and genetic disorders with multi-organ system defects such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, neurofibromatosis type 1, Costello syndrome, Nijmegen breakage syndrome, Rubinstein-Taybi syndrome, Dubowitz syndrome, multiple endocrine neoplasia type 2A, Roberts syndrome, and Duchenne muscular dystrophy. [15][16][17] Subtype classification and gene fusion status closely correlate with the prognosis. 18 However, a question remains, whether alveolar rhabdomyosarcoma cases without PAX3/7-FOXO1 fusion are truly negative for any gene fusion.…”