OBJECTIVE: Cantu Syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by GoF variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels, and is characterized by low systemic vascular resistance, as well as tortuous, dilated vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell-autonomously within vascular smooth muscle cells (VSMCs), or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs.
RESULTS: Whole-cell voltage-clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were consistent with those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance, and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae, and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs, suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF.
CONCLUSIONS: The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs.

Cantu syndrome is a rare and complex multisystem disorder characterized by hypertrichosis, facial dysmorphism, osteochondroplasia and cardiac abnormalities. With only 150 cases reported worldwide, Cantu syndrome is now gaining wider recognition due to molecular testing and a growing body of literature that further characterizes the syndrome and some of its most important features. Cardiovascular pathology previously described in the literature include cardiomegaly, pericardial effusion, vascular dilation and tortuosity, and other congenital heart defects. However, cardiovascular involvement is highly variable amongst individuals with Cantu syndrome. In some instances, it can be extensive and severe requiring surgical management and long term follow up.
Herein we report a case of a fourteen-year-old female who presented with worsening pericardial effusion of unknown etiology, and echocardiographic findings of concentric left ventricular hypertrophy, a mildly dilated aortic root and ascending aorta. Her medical history was notable for hemoptysis and an episode of pulmonary hemorrhage secondary to multiple aortopulmonary collaterals that were subsequently embolized in early childhood. She was initially managed with Ibuprofen and Colchicine but continued to worsen, and ultimately required a pericardial window for the management of refractory pericardial effusion. Imaging studies obtained on subsequent visits revealed multiple dilated and tortuous blood vessels in the head, neck, chest, and pelvis. A cardiomyopathy molecular studies panel was sent, and a pathogenic variant was identified in the ABCC9 gene, confirming the molecular diagnosis of autosomal dominant Cantu syndrome.
Vascular anomalies and significant cardiac involvement are often present in Cantu syndrome, however there are currently no established screening recommendations or surveillance protocols in place. The triad of hypertrichosis, facial dysmorphism, and unexplained cardiovascular involvement in any patient should raise suspicion for Cantu syndrome and warrant further investigation. Initial cardiac evaluation and follow up should be indicated in any patient with a clinical and/or molecular diagnosis of Cantu syndrome. Furthermore, whole body imaging should be utilized to evaluate the extent of vascular involvement and dictate long term monitoring and care.

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(1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in the ABCC9 and KCNJ8 genes, which encode ATP-sensitive K+ (KATP) channel subunits SUR2 and Kir6.1, respectively. Most CS patients have mutations in SUR2, the major component of skeletal muscle KATP, but the consequences of SUR2 GOF in skeletal muscle are unknown. (2) Methods: We performed in vivo and ex vivo characterization of skeletal muscle in heterozygous SUR2[A478V] (SUR2wt/AV) and homozygous SUR2[A478V] (SUR2AV/AV) CS mice. (3) Results: In SUR2wt/AV and SUR2AV/AV mice, forelimb strength and diaphragm amplitude movement were reduced; muscle echodensity was enhanced. KATP channel currents recorded in Flexor digitorum brevis fibers showed reduced MgATP-sensitivity in SUR2wt/AV, dramatically so in SUR2AV/AV mice; IC50 for MgATP inhibition of KATP currents were 1.9 ± 0.5 × 10-5 M in SUR2wt/AV and 8.6 ± 0.4 × 10-6 M in WT mice and was not measurable in SUR2AV/AV. A slight rightward shift of sensitivity to inhibition by glibenclamide was detected in SUR2AV/AV mice. Histopathological and qPCR analysis revealed atrophy of soleus and tibialis anterior muscles and up-regulation of atrogin-1 and MuRF1 mRNA in CS mice. (4) Conclusions: SUR2[A478V] \"knock-in\" mutation in mice impairs KATP channel modulation by MgATP, markedly so in SUR2AV/AV, with atrophy and non-inflammatory edema in different skeletal muscle phenotypes.

Cantu syndrome is an autosomal dominant disorder, first described by Cantu in 1982, that is characterized by congenital hypertrichosis, characteristic facial anomalies and cardiomegaly. Recent investigations have revealed that this syndrome is caused by mutations of ABCC9, which encodes a regulatory subunit of SUR2, an adenosine triphosphate-mediated potassium channel opener, expressed not only in smooth muscle but also in hair follicles. However, the abnormalities of skin and hair in patients with Cantu syndrome have not been well explored. We herein report three Japanese patients with Cantu syndrome and describe their specific skin manifestations and alterations in the histopathology of their hair follicles and sebaceous glands. Similar alterations were shared among those three patients and may be related to the function of SUR2, namely the regulation of hair follicle growth, because SUR2 is a known pharmacological target of minoxidil.

When encountering patients with markedly dilated and tortuous retinal vessels, Wyburn-Mason syndrome (WMS) or racemous angiomatosis (phacomatosis) is commonly thought of as the archetypal entity that can produce these findings. We describe a patient with Cantu syndrome with phenotypical findings identical to those seen in patients with WMS and want to highlight this as another entity that can present with tortuous and dilated retinal vessels.

The adenosine triphosphate-sensitive potassium (KATP) channel opener diazoxide (DZX) prevents myocyte volume derangement and reduced contractility secondary to stress. KATP channels are composed of pore-forming (Kir6.1 or Kir6.2) and regulatory (sulfonylurea receptor, SUR1 or SUR2) subunits. Gain of function (GOF) of Kir6.1 subunits has been implicated in cardiac pathology in Cantu syndrome in humans (cardiomegaly, lymphedema, and pericardial effusions). We hypothesized that GOF of Kir6.1 subunits would result in altered myocyte response to stress.
Isolated cardiac myocytes from wild type (WT) and transgenic Kir6.1GOF mice were exposed to Tyrode\'s physiologic solution for 20 min, test solution (Tyrode\'s or stress [hyperkalemic cardioplegia {CPG, known myocyte stress}] +/- KATP channel opener DZX), followed by Tyrode\'s for 20 min. Myocyte volume and contractility were measured and compared.
WT myocytes demonstrated significant swelling in response to stress, but significantly less swelling was seen in Kir6.1GOF myocytes. DZX prevented swelling secondary to CPG in WT but resulted in a nonsignificant reduction in swelling in Kir6.1GOF myocytes. Both WT and Kir6.1GOF myocytes demonstrated a reduction in contractility during stress, although this was only significant in Kir6.1GOF myocytes. DZX was not associated with an improvement in contractility in Kir6.1GOF myocytes following stress.
Similar to previous results in Kir6.1(-/-) myocytes, Kir6.1GOF myocytes demonstrate resistance (less volume derangement) to stress of cardioplegia. Understanding the role of Kir6.1 in myocyte response to stress may aid in the treatment of patients with Cantu syndrome and warrants further investigation.

ATP-sensitive potassium (KATP) channels play fundamental roles in the regulation of endocrine, neural and cardiovascular function. Small-molecule inhibitors (e.g., sulfonylurea drugs) or activators (e.g., diazoxide) acting on SUR1 or SUR2 have been used clinically for decades to manage the inappropriate secretion of insulin in patients with Type 2 diabetes, hyperinsulinism and intractable hypertension. More recently, the discovery of rare disease-causing mutations in KATP channel-encoding genes has highlighted the need for new therapeutics for the treatment of certain forms of neonatal diabetes mellitus, congenital hyperinsulinism and Cantu syndrome. Here, we provide a high-level overview of the pathophysiology of these diseases and discuss the development of a flexible high-throughput screening platform to enable the development of new classes of KATP channel modulators.

BACKGROUND: Gain-of-function (GOF) mutations in the KATP channel subunits Kir6.1 and SUR2 cause Cantu syndrome (CS), a disease characterized by multiple cardiovascular abnormalities.
OBJECTIVE: The purpose of this study was to better determine the electrophysiologic consequences of such GOF mutations in the heart.
METHODS: We generated transgenic mice (Kir6.1-GOF) expressing ATP-insensitive Kir6.1[G343D] subunits under α-myosin heavy chain (α-MHC) promoter control, to target gene expression specifically in cardiomyocytes, and performed patch-clamp experiments on isolated ventricular myocytes and invasive electrophysiology on anesthetized mice.
RESULTS: In Kir6.1-GOF ventricular myocytes, KATP channels showed decreased ATP sensitivity but no significant change in current density. Ambulatory ECG recordings on Kir6.1-GOF mice revealed AV nodal conduction abnormalities and junctional rhythm. Invasive electrophysiologic analyses revealed slowing of conduction and conduction failure through the AV node but no increase in susceptibility to atrial or ventricular ectopic activity. Surface ECGs recorded from CS patients also demonstrated first-degree AV block and fascicular block.
CONCLUSIONS: The primary electrophysiologic consequence of cardiac KATP GOF is on the conduction system, particularly the AV node, resulting in conduction abnormalities in CS patients who carry KATP GOF mutations.

Cantu syndrome is an autosomal dominant overgrowth syndrome associated with facial dysmorphism, congenital hypertrichosis, and cardiomegaly. Some affected individuals show bone undermodeling of variable severity. Recent investigations revealed that the disorder is caused by a mutation in ABCC9, encoding a regulatory SUR2 subunit of an ATP-sensitive potassium channel mainly expressed in cardiac and skeletal muscle as well as vascular smooth muscle. We report here on a Japanese family with this syndrome. An affected boy and his father had a novel missense mutation in ABCC9. Each patient had a coarse face and hypertrichosis. However, cardiomegaly was seen only in the boy, and macrosomia only in the father. Skeletal changes were not evident in either patient. Craniosynostosis in the boy and the development of aortic aneurysm in the father are previously undescribed associations with Cantu syndrome.