Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60% of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIPBL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2-interacting domain of NIPBL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS.
Mutations affecting the transcriptional regulator Ankyrin Repeat Domain 11 (ANKRD11) are mainly associated with the multisystem developmental disorder known as KBG syndrome, but have also been identified in individuals with Cornelia de Lange syndrome (CdLS) and other developmental disorders caused by variants affecting different chromatin regulators. The extensive functional overlap of these proteins results in shared phenotypical features, which complicate the assessment of the clinical diagnosis. Additionally, re‐evaluation of individuals at a later age occasionally reveals that the initial phenotype has evolved toward clinical features more reminiscent of a developmental disorder different from the one that was initially diagnosed. For this reason, variants in ANKRD11 can be ascribed to a broader class of disorders that fall within the category of the so‐called chromatinopathies. In this work, we report on the clinical characterization of 23 individuals with variants in ANKRD11. The subjects present primarily with developmental delay, intellectual disability and dysmorphic features, and all but two received an initial clinical diagnosis of either KBG syndrome or CdLS. The number and the severity of the clinical signs are overlapping but variable and result in a broad spectrum of phenotypes, which could be partially accounted for by the presence of additional molecular diagnoses and distinct pathogenic mechanisms.
Background: Little is known about the mortality and utilization outcomes of short-stay intensive care unit (ICU) patients who require <24 h of critical care. We aimed to define characteristics and outcomes of short-stay ICU patients whose need for ICU level-of-care is ≤24 h compared to nonshort-stay patients. Methods: Single-center retrospective cohort study of patients admitted to the medical ICU at an academic tertiary care center in 2019. Fisher's exact test or Chi-square for descriptive categorical variables, t -test for continuous variables, and Mann–Whitney two-sample test for length of stay (LOS) outcomes. Results: Of 819 patients, 206 (25.2%) were short-stay compared to 613 (74.8%) nonshort-stay. The severity of illness as measured by the Mortality Probability Model-III was significantly lower among short-stay compared to nonshort-stay patients ( P = 0.0001). Most short-stay patients were admitted for hemodynamic monitoring not requiring vasoactive medications (77, 37.4%). Thirty-six (17.5%) of the short-stay cohort met Society of Critical Care Medicine's guidelines for ICU admission. Nonfull-ICU LOS, or time spent waiting for transfer out to a non-ICU bed, was similar between the two groups. Hospital mortality was lower among short-stay patients compared to nonshort-stay patients ( P = 0.01). Conclusions: Despite their lower illness severity and fewer ICU-level care needs, short-stay patients spend an equally substantial amount of time occupying an ICU bed while waiting for a floor bed as nonshort-stay patients. Further investigation into the factors influencing ICU triage of these subacute patients and contributors to system inefficiencies prohibiting their timely transfer may improve ICU resource allocation, hospital throughput, and patient outcomes.
INTRODUCTION: Basal Cell Adenocarcinoma (BCAC) is a relatively rare malignancy, accounting for approximately 2% of all salivary neoplasms. BCAC can occasionally cause invasive disease and infrequently, metastatic disease. Most common sites of metastases in BCAC include cervical lymph nodes with sparse reports of pulmonary, hepatic and cutaneous involvement. Here, we present a case of endobronchial metastases from BCAC of the base of the tongue. CASE PRESENTATION: A 76 y.o. male with a past medical history of BCAC who underwent right tongue base excision followed by adjuvant radiotherapy in 2018 who presented with a one-day history of hemoptysis. Two weeks prior to presentation, he underwent a CT-guided lung biopsy for a right upper lobe nodule that was nondiagnostic. He was then transferred to an academic medical center for further evaluation.On presentation, he felt well overall and had not experienced any additional occurrences of hemoptysis. CT chest revealed enlarging mediastinal lymph nodes causing severe stenosis of the bronchus intermedius and right lower lobe bronchus.On hospital day 2, he underwent bronchoscopy that revealed involvement of the bronchus intermedius resulting in approximately 80% luminal compromise. Tumor debulking and tracheal stenting was performed. Following discharge, PET scan confirmed malignant involvement. Pathology revealed a basaloid epithelial neoplasm morphologically similar to the prior tongue biopsy. Histology revealed an exceptionally high proliferation index (Ki67 > 90%). The decision was made to pursue palliative radiotherapy followed by pembrolizumab monotherapy. The patient expired approximately two months after diagnosis. DISCUSSION:The management of BCAC, as with all salivary gland neoplasms, is particularly challenging due to the phenotypic heterogeneity and low clinical incidence. The most common strategy includes surgical resection with adjuvant radiotherapy. While distant metastases is an uncommon recurrence, local recurrence is quite common despite tumor-free surgical margins with rates of upward to 50%. Chemotherapy has been found to be of limited use, predominately in the setting of recurrent or metastatic disease. Currently, there are no National Comprehensive Care Network (NCCN) recommendations for specific regimens. The most common agents include cisplatin, doxorubicin with either 5-fluorouracil or cyclophosphamide. However, no regimen has produced significant and reproducible improvements in overall survival or disease-free survival.CONCLUSIONS: This case demonstrates several unique features. This patient did not experience local recurrence, but rather distant metastasis to a novel location. Also, this patient featured an exceptionally high proliferation index, indicating that BCAC has the potential for clinical heterogeneity. Finally, this case highlights the need for further research into the role of imaging surveillance during remission.
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