Autosomal Dominant Osteopetrosis (ADO) caused by a Missense Variant in the TCIRG1 Gene.

CONTEXT: Autosomal dominant osteopetrosis (ADO) is a rare genetic disorder due to impaired osteoclastic bone resorption. Clinical manifestations frequently include fractures, osteonecrosis (particularly of the jaw or maxilla), osteomyelitis, blindness, and/or bone marrow failure. ADO usually results from heterozygous missense variants in the Chloride Channel 7 gene (CLCN7) that cause disease by a dominant negative mechanism. Variants in the T cell immune regulator 1 gene (TCIRG1) are commonly identified in autosomal recessive osteopetrosis but have only been reported in one patient with ADO. CASE DESCRIPTION: Here we report 3 family members with a single heterozygous missense variant (p.Gly579Arg) in TCIRG1 who have a phenotype consistent with ADO. Three of five protein prediction programs suggest this variant likely inhibits the function of TCIRG1. CONCLUSIONS: This is the first description of adult presentation of ADO caused by a TCIRG1 variant. Similar to families with ADO from CLCN7 mutations, this variant in TCIRG1 results in marked phenotype variability, with two subjects having severe disease and the third having very mild disease. This family report implicates TCIRG1 missense mutations as a cause of ADO and demonstrates that the marked phenotypic variability in ADO may extend to disease caused by TCIRG1 missense mutations.

The Use of Inhaled Epoprostenol for Acute Respiratory Distress Syndrome Secondary Due To COVID-19: a Case Series.

Introduction: Inhaled epoprostenol (iEpo) is a pulmonary vasodilator used to treat refractory respiratory failure, including that caused by Coronavirus 2019 (COVID-19) pneumonia. Aim of Study: To describe the experience at three teaching hospitals using iEpo for severe respiratory failure due to COVID-19 and evaluate its efficacy in improving oxygenation. Methods: Fifteen patients were included who received iEpo, had confirmed COVID-19 and had an arterial blood gas measurement in the 12 hours before and 24 hours after iEpo initiation. Results: Eleven patients received prone ventilation before iEpo (73.3%), and six (40%) were paralyzed. The partial pressure of arterial oxygen to fraction of inspired oxygen (P/F ratio) improved from 95.7 mmHg to 118.9 mmHg (p=0.279) following iEpo initiation. In the nine patients with severe ARDS, the mean P/F ratio improved from 66.1 mmHg to 95.7 mmHg (p=0.317). Ultimately, four patients (26.7%) were extubated after an average of 9.9 days post-initiation. Conclusions: The findings demonstrated a trend towards improvement in oxygenation in critically ill COVID-19 patients. Although limited by the small sample size, the results of this case series portend further investigation into the role of iEpo for severe respiratory failure associated with COVID-19.