Glibenclamide treatment in a Cantú syndrome patient with a pathogenic ABCC9 gain‐of‐function variant: Initial experience |
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| Authors: | Alan Ma Sunita Gurnasinghani Edwin P. Kirk Conor McClenaghan Gautam K. Singh Dorothy K. Grange Chetan Pandit Yung Zhu Tony Roscioli George Elakis Michael Buckley Bhavesh Mehta Philip Roberts Jonathan Mervis Andrew Biggin Colin G. Nichols |
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| Affiliation: | 1. Department of Clinical Genetics, Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, New South Wales, Australia;2. Discipline of Genomic Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia;3. Centre for Clinical Genetics, Sydney Children's Hospital, Sydney Children's Hospital Network, Sydney, New South Wales, Australia;4. NSW Health Pathology East Genomics Laboratory, Sydney, New South Wales, Australia;5. School of Women's and Children's Health, University of NSW, Sydney, New South Wales, Australia;6. Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri;7. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri;8. Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri;9. Department of Respiratory and Sleep Medicine, The Children's Hospital at Westmead, Sydney, New South Wales, Australia;10. Grace Centre for Newborn Intensive Care, The Children's Hospital at Westmead, Sydney, New South Wales, Australia;11. Department of Cardiology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia;12. Children's Hospital Westmead Clinical School, University of Sydney, New South Wales, Australia;13. Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia;14. https://orcid.org/0000-0002-4929-2134;15. Colin G. Nichols, Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. |
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| Abstract: | Cantú syndrome (CS), characterized by hypertrichosis, distinctive facial features, and complex cardiovascular abnormalities, is caused by pathogenic variants in ABCC9 and KCNJ8 genes. These genes encode gain‐of‐function mutations in the regulatory (SUR2) and pore‐forming (Kir6.1) subunits of KATP channels, respectively, suggesting that channel‐blocking sulfonylureas could be a viable therapy. Here we report a neonate with CS, carrying a heterozygous ABCC9 variant (c.3347G>A, p.Arg1116His), born prematurely at 32 weeks gestation. Initial echocardiogram revealed a large patent ductus arteriosus (PDA), and high pulmonary pressures with enlarged right ventricle. He initially received surfactant and continuous positive airway pressure ventilation and was invasively ventilated for 4 weeks, until PDA ligation. After surgery, he still had ongoing bilevel positive airway pressure (BiPAP) requirement, but was subsequently weaned to nocturnal BiPAP. He was treated for pulmonary hypertension with Sildenafil, but failed to make further clinical improvement. A therapeutic glibenclamide trial was commenced in week 11 (initial dose of 0.05 mg–1 kg–1 day–1 in two divided doses). After 1 week of treatment, he began to tolerate time off BiPAP when awake, and edema improved. Glibenclamide was well tolerated, and the dose was slowly increased to 0.15 mg?1 kg?1day?1 over the next 12 weeks. Mild transient hypoglycemia was observed, but there was no cardiovascular dysfunction. Confirmation of therapeutic benefit will require studies of more CS patients but, based on this limited experience, consideration should be given to glibenclamide as CS therapy, although problems associated with prematurity, and complications of hypoglycemia, might limit outcome in critically ill neonates with CS. |
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| Keywords: | BiPAP cardiomegaly continuous positive airway pressure hypertrichosis osteodysplasia patent ductus arteriosus sulfonylurea |
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