TY - JOUR
T1 - Glibenclamide treatment in a Cantú syndrome patient with a pathogenic ABCC9 gain-of-function variant
T2 - Initial experience
AU - Ma, Alan
AU - Gurnasinghani, Sunita
AU - Kirk, Edwin P.
AU - McClenaghan, Conor
AU - Singh, Gautam K.
AU - Grange, Dorothy K.
AU - Pandit, Chetan
AU - Zhu, Yung
AU - Roscioli, Tony
AU - Elakis, George
AU - Buckley, Michael
AU - Mehta, Bhavesh
AU - Roberts, Philip
AU - Mervis, Jonathan
AU - Biggin, Andrew
AU - Nichols, Colin G.
N1 - Publisher Copyright:
© 2019 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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.
KW - BiPAP
KW - cardiomegaly
KW - continuous positive airway pressure
KW - hypertrichosis
KW - osteodysplasia
KW - patent ductus arteriosus
KW - sulfonylurea
UR - http://www.scopus.com/inward/record.url?scp=85067397492&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.61200
DO - 10.1002/ajmg.a.61200
M3 - Article
C2 - 31175705
AN - SCOPUS:85067397492
SN - 1552-4825
VL - 179
SP - 1585
EP - 1590
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 8
ER -