Syndromic Involvement of Patients Presenting With Congenital Upper Limb Anomalies: An Analysis of 4,317 Cases.

PURPOSE: This study investigated the patterns of syndromic involvement for patients with congenital upper limb anomalies (CULAs). We hypothesize that patients with CULAs will present with predictable syndromic patterns. METHODS: This retrospective study queried the multicenter Congenital Upper Limb Differences (CoULD) Registry. Of the 4,317 patients enrolled, 578 (13%) reported one or more syndromes. Syndromes were confirmed to be recognized by the Online Mendelian Inheritance in Man. Demographics were reviewed and compared with the full CoULD registry group. Syndromes reported by five or more patients were examined to determine the type of CULA according to Oberg/Manske/Tonkin classifications. RESULTS: Of the 578 children with one or more reported syndromes, 517 had Online Mendelian Inheritance in Man recognized syndromes (cohort A), In cohort A, 58 syndromes were each represented by a single patient within the registry. Forty-eight syndromes in cohort A were reported by two or more patients, which accounted for 461 of the total patients with reported syndromes. However, VACTERL and Poland syndromes were the most commonly reported syndromes. Patients with CULAs and syndromes frequently exhibited bilateral involvement (61%), compared with the entire CoULD group (47%) and other orthopedic (50%) and medical conditions (61%) compared with the entire CoULD group (24% and 27%, respectively). Additionally, they exhibited a lower frequency of family history of a congenital orthopedic condition (21%) or a family member with the same CULA (9%) compared with the entire CoULD group (26% and 14%, respectively). CONCLUSIONS: Associated syndromes were recorded in 578 patients (13%) in the CoULD registry as follows: 58 syndromes represented by a single patient, 48 by 2 or more patients, and 23 syndromes by 5 or more patients. Rare syndromes that are only represented by a single patient are more likely to be unknown by a pediatric hand surgeon, and consultation with a geneticist is advised. TYPE OF STUDY/LEVEL OF EVIDENCE: Differential Diagnosis/Symptom Prevalence Study IV.

Exosome-educated macrophages and exosomes differentially improve ligament healing.

Recently, our group used exosomes from mesenchymal stromal/stem cells (MSCs) to simulate an M2 macrophage phenotype, that is, exosome-educated macrophages (EEMs). These EEMs, when delivered in vivo, accelerated healing in a mouse Achilles tendon injury model. For the current study, we first tested the ability of EEMs to reproduce the beneficial healing effects in a different rodent model, that is, a rat medial collateral ligament (MCL) injury model. We hypothesized that treatment with EEMs would reduce inflammation and accelerate ligament healing, similar to our previous tendon results. Second, because of the translational advantages of a cell-free therapy, exosomes alone were also examined to promote MCL healing. We hypothesized that MSC-derived exosomes could also alter ligament healing to reduce scar formation. Similar to our previous Achilles tendon results, EEMs improved mechanical properties in the healing ligament and reduced inflammation, as indicated via a decreased endogenous M1/M2 macrophage ratio. We also showed that exosomes improved ligament remodeling as indicated by changes in collagen production and organization, and reduced scar formation but without improved mechanical behavior in healing tissue. Overall, our findings suggest EEMs and MSC-derived exosomes improve healing but via different mechanisms. EEMs and exosomes each have attractive characteristics as therapeutics. EEMs as a cell therapy are terminally differentiated and will not proliferate or differentiate. Alternatively, exosome therapy can be used as a cell free, shelf-stable therapeutic to deliver biologically active components. Results herein further support using EEMs and/or exosomes to improve ligament healing by modulating inflammation and promoting more advantageous tissue remodeling.