Two Novel Mutations of ANKRD11 Gene and Wide Clinical Spectrum in KBG Syndrome: Case Reports and Literature Review

Abstract

Background KBG syndrome (OMIM #148050) is a rare, autosomal dominant inherited genetic disorder caused by heterozygous mutations in the ankyrin repeat domain-containing protein 11 (ANKRD11) gene or by microdeletion of chromosome 16q24.3. It is characterized by macrodontia of the upper central incisors, distinctive facial dysmorphism, short stature, vertebral abnormalities, hand anomaly including clinodactyly, and various degrees of developmental delay. KBG syndrome presents with variable clinical feature and severity among individuals. Here, we report two KBG patients who have different novel heterozygous mutations of ANKRD11 gene with wide range of clinical manifestations. Case presentation Two novel heterozygous mutations of ANKRD11 gene were identified in two unrelated Korean patients with variable clinical presentations. The first patient presented with short stature and early puberty and was treated with growth hormone and gonadotropin-releasing hormone agonist without adverse effects. He had mild intellectual disability. In targeted exome sequencing, a novel de novo frameshift variant was identified in ANKRD11, c.5889del, and p. (Ile1963MetfsX9). The second patient had severe intellectual disability with epilepsy. He had normal height and prepubertal stage at the age of 11 years. He had behavioral problems such as autism-like features, anxiety, and stereotypical movements. Whole exome sequencing (WES) was performed, and the novel heterozygous mutation, c3310dup, p. (Glu110GlyfsTer5) in ANKRD11 was identified. Conclusion KBG syndrome is often underdiagnosed because of its non-specific features and phenotypic variability. Performing a next—generation sequencing panel, including the ANKRD11 gene for cases of developmental delay with/without short stature may be helpful to identify hitherto undiagnosed KBG syndrome patients.

A de novo frameshift variant of ANKRD11 (c.1366_1367dup) in a Chinese patient with KBG syndrome

“…The prevalence of this disease remains unknown. To date, more than 200 patients with KBG syndrome have been reported worldwide [ 7 ]. However, it is likely that this syndrome is underdiagnosed, since many of the features are mild and do not specific to this syndrome [ 2 ].…”

Case Report: Two Newly Diagnosed Patients With KBG Syndrome—Two Different Molecular Changes

“…There are almost 200 patients with KBG syndrome reported in the literature since 1975 (1,2). The prevalence of the disorder has not yet been established (3).…”

“…Pathogenic variants in ANKRD11 gene account for most cases (5,6). Clinical diagnostic criteria include: (1) macrodontia of the upper central incisors, which is reported in more than 95% of cases and considered a distinctive trait of KBG syndrome; (2) characteristic facial features; (3) hand abnormalities, (fifth finger clinodactyly, clinical brachydactyly, or short tubular bones on the radiographic exam); (4) neurological problems, global developmental delay, and/or a seizure disorder, (5) bone age >2 SD below average; (6) costovertebral abnormalities, (abnormal curvature of the spine, cervical ribs, or vertebral/endplate defects); (7) postnatal short stature (as a height less than 3rd centile); and (8) occurrence of a first-degree relative affected by KBG syndrome (7). The patient should fulfill four or more of these eight criteria (7).…”

“…The patient should fulfill four or more of these eight criteria (7). The ANKRD11 gene encodes ankyrin repeat domain 11, a protein which contains multiple ankyrin domains 1 . Cell line studies indicate that Ankrd11 is a nuclear protein which regulates transcription by binding chromatin-modifying enzymes such as histone deacetylases.…”

Clinical and genetic characteristics of Keishi-Bukuryo-Gan syndrome: an analysis of 5 cases

“…[Key words]Genetic diseases, inborn；Keishi-Bukuryo-Gansyndrome；ANKRD11 gene；Phenotype；Growth retardation；Recombinant human growth hormone [2][3][4] ，属于罕见的遗传性疾病。2011 年，Sirmaci 等 [5] 证实 KBG 综合征 是由于 ANKRD11 基因突变或包含 ANKRD11 基因的 16q24.3 缺失引起，通常为常染色体显性遗传。但随着 病例增多，发现男性病例居多且表型重，女性病例少见且表型轻，因此有学者提出 KBG 综合征可能为 X 连锁遗传 [6] [6][7][9][10][11] ：50%以上的患儿有认知障碍、永久性大上中切牙、特殊面容(三角脸、浓眉、长人中、薄 上唇、眼距宽)、骨骼异常、脑电图异常或脑部发育异常、身材矮小或生长减速等表现；少见表现包括进 食问题(20%)、听力问题(25％～31％)、隐睾(25％～35％)、先天性心脏病(10％～26％)、行为 或性格异常等。本文资料中的 5 例患儿大多数符合上述体征。除此之外，所有患儿前囟大或前囟闭合延迟 (100%)表现突出，其中例 2 在半岁时曾因为前囟大就诊。Karen Low 等 [6] 认为前囟大是婴儿期早期诊断 KBG 综合征的线索之一。此外，本组病例还出现一些特殊的表型，主要为外耳及皮肤、足弓异常。既往文 献报道 KBG 综合征患儿可出现耳廓发育不良，而本组患儿仅例 2 耳廓发育不良，其余 4 例患儿为大耳、耳 唇厚，耳廓向前外旋 [9] 。另外 例不同家系的患儿均出现足部发育异常(足跟小、足弓塌陷、行走时双足 内翻)，也为文献罕见报道的体征。皮肤白斑、蒙古斑、毛囊角化等表现在以往报道的病例中也较为少见， 丰富了 KBG 综合征的表型谱。值得注意的是，KBG 综合征患儿的面容特征可以随年龄出现变化，不同发 育期面部特征、毛发有差异，6 岁前面容特征可能不典型，易导致漏诊 [6] 。 [2][3][4]9] 。 目前认为，KBG 综合征基因型与表型谱无显著相关性 [5] 。例 3 为已报道的 c.3770_3771delAA 突变，并 无上中切牙宽大及听力问题，与文献报道有差异，可能与患儿年龄小有关 [11] ，有待进一步随访观察。例 4、例 5 为同卵双胎，携带相同的 ANKRD11 突变位点，但例 4 合并先心病，且宫内发育迟缓、神经系统损 伤较例 5 严重，两例患儿表型不同考虑与 ANKRD11 突变位点外显率有关，或存在体细胞嵌合 [12] 。鉴于此， 先证者的亲本和同胞应进行突变位点的检测，应注重产前咨询。需要注意的是，KBG 综合征少部分由包含 ANKRD11 基因的 16q24.3 缺失导致，当临床高度怀疑 KBG 综合征时，可以先进行 ANKRD11 基因 Sanger 测 序检测突变位点 [5] ，阴性者再进行全外显子组基因测序；因 KBG 综合征的临床表现与德朗热综合征、歌舞 伎综合征等类似，鉴别诊断困难，对普通疑似 KBG 综合征病例，建议直接行全外显子组基因测序，有利 于发现共存的其他基因缺陷 [6,11] 。如全外显子组基因测序仍为阴性，建议行基因芯片检测确定是否存在 16q24.3 缺失。 目前，KBG 综合征是否出现宫内发育迟缓仍有争议，但患儿出生后生长发育落后，逐渐偏离遗传曲线 为其主要表现之一 [5] 。本文资料中的 例患儿均以生长发育落后就诊于内分泌遗传代谢科，甲状腺功能、 皮质醇、胰岛素样生长因子 1、胰岛素等内分泌评估均正常，与文献报道相符 [2] 。目前，rhGH 越来越多地 应用于遗传性综合征，对改善患儿的认知功能，促进身高正常化有较好疗效 [13] 。2015 年，Reynaert 等 [13] 首 次报道了 KBG 综合征患者应用 rhGH 治疗后的反应，并提出 KBG 综合征患儿无论是否存在生长激素缺乏 症，外源性生长激素都有希望成为治疗 KBG 综合征患儿身材矮小的有效方法。研究初步证明，rhGH 治疗 可有效改善身材矮小的 KBG 综合征患儿的身高 [2,9,14]…”