Glibenclamide treatment in a Cantú syndrome patient with a pathogenic ABCC9 gain‐of‐function variant: Initial experience

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.

Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity

“…Consistent with this, a mild glucose intolerance phenotype was observed in high-dose-treated WT and SUR2 wt/AV mice (Figure 3, G and H). Notably, in a single human CS case thus far treated with glibenclamide, transient hypoglycemia only was also observed at initiation of glibenclamide treatment or dose escalation (22), and thus chronic hypoglycemia may not prove to be a significant complication for glibenclamide therapy in patients with CS.…”

Three‐dimensional facial morphology in Cantú syndrome

“…Subsequent molecular analysis of such patients may identify mutations and in combination with detailed facial analysis enable unequivocal identification of causative genes. Considering the current efforts to develop a pharmacological treatment for CS (Ma et al, ; McClenaghan et al, ), 3D technology additionally may enable the evaluation and quantitative measurement of effective response to therapy options in the future which will possibly lead to a decrease in coarseness of the face.…”

Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension

“…Cantu Syndrome is characterized by congenital hypertrichosis, osteochondroplasia, and cardiac defects, such as cardiomegaly, dilated vasculature, tortuous vasculature, and pericardial effusion. Interestingly, some patients have also developed PH [ 108 , 109 ]. To date, 12 different mutations in ABCC9 have been identified in Cantu Syndrome.…”

“…To date, 12 different mutations in ABCC9 have been identified in Cantu Syndrome. Electrophysiological recordings have demonstrated that ABCC9 mutations are gain-of-function mutations [ 108 , 109 , 110 , 111 , 112 ]. The primary opening of SUR2A/Kir6.1 leads to systemic vasorelaxation and hypotension, and the secondary opening of SUR2A/Kir6.1 leads to compensatory cardiac hypertrophy and hypercontractility [ 113 ].…”

“…A potential treatment for Cantu Syndrome patients with PH may be sulfonylurea receptor inhibitors, such as glibenclamide or mimoxidil. However precaution should be taken due to the potential side effect on SUR1 in the pancreas [ 108 , 109 ] and lung [ 79 ].…”