A Unique Clinical Presentation of Congenital Thumb Aplasia, Radioulnar Synostosis, and Chiari Malformation: A Potential Pediatric Syndromic Association.

The medical literature does not currently report a case of co-occurring congenital thumb aplasia, radioulnar synostosis (RUS), and Chiari malformation with scoliosis. Furthermore, there is an overlap of clinical features with other documented syndromes and associations that have potential cardiac, gastrointestinal, hematologic, and nephrological implications, thus contributing to increased morbidity and mortality if left undetected. We describe an interesting case of congenital thumb aplasia, RUS, and Chiari malformation with scoliosis in the absence of non-musculoskeletal abnormalities. These findings prompted further investigation to determine whether this is a unique presentation of a previously described syndrome, due to teratogenic exposure in utero, or a syndromic association yet to be adequately identified by the scientific community. We also identified several candidate genes that may guide genetic testing in the future.

Smad8 Is Increased in Duchenne Muscular Dystrophy and Suppresses miR-1, miR-133a, and miR-133b.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterized by skeletal muscle instability, progressive muscle wasting, and fibrosis. A major driver of DMD pathology stems from aberrant upregulation of transforming growth factor ß (TGFß) signaling. In this report, we investigated the major transducers of TGFß signaling, i.e., receptor Smads (R-Smads), in DMD patient skeletal muscle and observed a 48-fold increase in Smad8 mRNA. Smad1, Smad2, Smad3, and Smad5 mRNA were only minimally increased. A similar pattern was observed in the muscle from the mdx5cv mouse. Western blot analysis showed upregulation of phosphorylated Smad1, Smad5, and Smad8 compared to total Smad indicating activation of this pathway. In parallel, we observed a profound diminishment of muscle-enriched microRNAs (myomiRs): miR-1, miR-133a, and miR-133b. The pattern of Smad8 induction and myomiR suppression was recapitulated in C2C12 muscle cells after stimulation with bone morphogenetic protein 4 (BMP4), a signaling factor that we found upregulated in DMD muscle. Silencing Smad8 in C2C12 myoblasts derepressed myomiRs and promoted myoblast differentiation; there was also a concomitant upregulation of myogenic regulatory factors (myogenin and myocyte enhancer factor 2D) and suppression of a pro-inflammatory cytokine (interleukin-6). Our data suggest that Smad8 is a negative regulator of miR-1, miR-133a, and miR-133b in muscle cells and that the BMP4-Smad8 axis is a driver of dystrophic pathology in DMD.