Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Eur J Med Genet. 2020 Sep;63(9):103996. doi: 10.1016/j.ejmg.2020.103996. Epub 2020 Jul 2.
Cantú syndrome (CS) is a rare developmental disorder characterized by a coarse facial appearance, macrocephaly, hypertrichosis, skeletal and cardiovascular anomalies and caused by heterozygous gain-of-function variants in ABCC9 and KCNJ8, encoding subunits of heterooctameric ATP-sensitive potassium (K) channels. CS shows considerable clinical overlap with Zimmermann-Laband syndrome (ZLS), a rare condition with coarse facial features, hypertrichosis, gingival overgrowth, intellectual disability of variable degree, and hypoplasia or aplasia of terminal phalanges and/or nails. ZLS is caused by heterozygous gain-of-function variants in KCNH1 or KCNN3, and gain-of-function KCNK4 variants underlie the clinically similar FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) syndrome; KCNH1, KCNN3 and KCNK4 encode potassium channels. Within our research project on ZLS, we performed targeted Sanger sequencing of ABCC9 in 15 individuals tested negative for a mutation in the ZLS-associated genes and found two individuals harboring a heterozygous pathogenic ABCC9 missense variant. Through a collaborative effort, we identified a total of nine individuals carrying a monoallelic ABCC9 variant: five sporadic patients and four members of two unrelated families. Among the six detected ABCC9 missense variants, four [p.(Pro252Leu), p.(Thr259Lys), p.(Ala1064Pro), and p.(Arg1197His)] were novel. Systematic assessment of the clinical features in the nine cases with an ABCC9 variant highlights the significant clinical overlap between ZLS and CS that includes early developmental delay, hypertrichosis, gingival overgrowth, joint laxity, and hypoplasia of terminal phalanges and nails. Gain of K channel activity possibly accounts for significant clinical similarities of CS, ZLS and FHEIG syndrome and defines a new subgroup of potassium channelopathies.
坎图综合征（CS）是一种罕见的发育障碍，其特征为面部粗糙、大头畸形、多毛症、骨骼和心血管异常，由 ABCC9 和 KCNJ8 的杂合功能获得性变异引起，这两个基因编码异源八聚体 ATP 敏感性钾（K）通道的亚基。CS 与齐默尔曼-兰博综合征（ZLS）表现出显著的临床重叠，ZLS 是一种罕见的疾病，具有粗糙的面部特征、多毛症、牙龈增生、不同程度的智力障碍、末端指（趾）骨和/或指甲发育不全或缺失。ZLS 是由 KCNH1 或 KCNN3 的杂合功能获得性变异引起的，而功能获得性 KCNK4 变异则导致临床相似的 FHEIG（面部畸形、多毛症、癫痫、智力障碍/发育迟缓、牙龈增生）综合征；KCNH1、KCNN3 和 KCNK4 编码钾通道。在我们对 ZLS 的研究项目中，我们对 15 名经 ZLS 相关基因突变检测为阴性的个体进行了 ABCC9 的靶向 Sanger 测序，发现两名个体携带杂合致病性 ABCC9 错义变异。通过合作，我们共发现 9 名个体携带单等位基因 ABCC9 变异：5 名散发性患者和 2 个不相关家族的 4 名成员。在检测到的 6 种 ABCC9 错义变异中，有 4 种（p.(Pro252Leu)、p.(Thr259Lys)、p.(Ala1064Pro)和 p.(Arg1197His)）是新发现的。对 9 例 ABCC9 变异患者的临床特征进行系统评估，突出了 ZLS 和 CS 之间显著的临床重叠，包括早期发育迟缓、多毛症、牙龈增生、关节松弛以及末端指（趾）骨和指甲发育不全。K 通道活性的增加可能是 CS、ZLS 和 FHEIG 综合征的显著临床相似的原因，并定义了钾通道病的一个新亚组。
