RESUMO
Objectives: Clefts of the lip, alveolus and/or palate (CLA/P) are the most common craniofacial congenital malformations in humans. These oral clefts can be divided into non-syndromic (isolated) and syndromic forms. Many cleft-related syndromes are clinically variable and genetically heterogeneous, making it challenging to distinguish syndromic from non-syndromic cases. Recognition of syndromic/genetic causes is important for personalized tailored care, identification of (unrecognized) comorbidities, and accurate genetic counseling. Therefore, next generation sequencing (NGS)-based targeted gene panel testing is increasingly implemented in diagnostics of CLA/P patients. In this retrospective study, we assess the yield of NGS gene panel testing in a cohort of CLA/P cases. Methods: Whole exome sequencing (WES) followed by variant detection and interpretation in an a priori selected set of genes associated with CLA/P phenotypes was performed in 212 unrelated CLA/P patients after genetic counseling between 2015 and 2020. Medical records including family history and results of additional genetic tests were evaluated. Results: In 24 CLA/P cases (11.3%), a pathogenic genetic variant was identified. Twenty out of these 24 had a genetic syndrome requiring specific monitoring and follow-up. Six of these 24 cases (25%) were presumed to be isolated CLA/P cases prior to testing, corresponding to 2.8% of the total cohort. In eight CLA/P cases (3.8%) without a diagnosis after NGS-based gene panel testing, a molecular diagnosis was established by additional genetic analyses (e.g., SNP array, single gene testing, trio WES). Conclusion: This study illustrates NGS-based gene panel testing is a powerful diagnostic tool in the diagnostic workup of CLA/P patients. Also, in apparently isolated cases and non-familial cases, a genetic diagnosis can be identified. Early diagnosis facilitates personalized care for patients and accurate genetic counseling of their families.
RESUMO
Patients with extensive and complex wounds due to Necrotizing Soft-Tissue Infections (NSTI) may be referred to a burn center. This study describes the characteristics, outcomes, as well as diagnostic challenges of these patients. Patients admitted to three hospitals with a burn center for the treatment of NSTI in a 5-year period were included. Eighty patients (median age 54 years, 60% male) were identified, of whom 30 (38%) were referred by other centers, usually after survival of the initial septic phase. Those referred from other centers, compared to those primarily admitted to the study hospitals, were more likely to have group A streptococcal involvement (62% vs 35%, p = .02), larger wounds (median 7% vs 2% total body surface area, p < .001), and a longer length of stay (median 49 vs 22 days, p < .001). Despite a high incidence of septic shock (50%), the mortality rate was low (12%) for those primarily admitted. Approximately half (53%) of the patients were initially misdiagnosed upon presentation, which was associated with delay to first surgery (16 hours vs 4 hours, p < .001). Those initially misdiagnosed had more (severe) comorbidities, and less frequently reported pain or blue livid discoloration of the skin. This study underlines the burn centers' function as referral centers for extensively affected patients with NSTI. Besides the unique wound and reconstructive expertise, the low mortality rate indicates these centers provide adequate acute care as well. A major remaining challenge remains recognition of the disease upon presentation. Future studies in which factors associated with misdiagnosis are explored are needed.
