In some cases this was the presenting feature and led to consideration of cleidocranial dysostosis (MIM # 119600). Several ANKRD11 gene mutations have been found to cause KBG syndrome, a condition characterized by large upper front teeth and other unusual facial features, skeletal abnormalities, and intellectual disability. 1. National Library of Medicine GeneReviews® [Internet]. Severe feeding issues; infections, lacrimal duct surgery; pain insensitivity, Array CGH for 16q24 microdeletion if KBG phenotype and, Hospital or community paediatrician for children and GP for adults, Investigations to consider in all patients, Referrals and on‐going surveillance that may be required, Neurology for seizures and movement disorders, Endocrinology for investigation of short stature if present, ENT/audiology for recurrent otitis media and/or hearing loss, Paediatric MDT assessment for developmental delay, ASD/ADHD and complex behaviour patterns, Investigations that may be indicated in individual patients. He also had two hair whorls on left and right sides of the occiput and a low V‐shaped posterior hairline. We paid particular attention to learning difficulties and behavioral phenotype which are often significant in KBG syndrome [Lo‐Castro et al., 2013]. Fundamental findings are: mild development delay, short stature, craniofacial dysmorphism and skeletal anomalies. 2) we identified in some but not all patients a triangular face, almond‐shaped palpebral fissures which may slant upwards, synophrys, prominent ears, a high nasal bridge and bulbous nasal tip, prominent cheekbones, a smooth philtrum with thin upper lip, prominent corners of the mouth, and facial hypertrichosis/low hairlines. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. Four patients attended a school for children with special needs and four went to a mainstream school but within a specified special needs unit (two within an autism unit). All patients in this study had a mutation in ANKRD11, a member of a family of Ankyrin repeat containing cofactors described a decade ago [Zhang et al., 2004] which is expressed in a wide variety of tissues including the brain. Our study clearly shows a predisposition for recurrent otitis media in KBG syndrome. Seattle (WA): University of Washington, Seattle; 1993–2021. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. KBG syndrome (MIM # 148050) [Herrmann et al., 1975] combines short‐stature, macrodontia of the permanent central upper incisors, distinctive facial features, learning difficulties, and neurobehavioral problems [Herrmann et al., 1975; Smithson et al., 2000; Skjei et al., 2007; Sirmaci et al., 2011; Youngs et al., 2011]. FOIA Coding regions of the ANKRD11 gene (13 exons including intron/exon boundaries extending to the branch sites) were amplified in 27 fragments using a MegaMix (MicroZone). Macrodontia of permanent upper central incisors was seen in 85%. One patient required tympanic membrane grafts at the age of 13 and another had sensorineural hearing loss in the context of a positive maternal family history. . Ansari et al. We alert clinicians to the key features of KBG syndrome including a wide fontanelle, which may be the first indication that an infant is affected. Subjective appraisal of the images confirmed the presence of characteristic facial features in some but not all patients. All but two patients consented to clinical photographs. In: StatPearls [Internet]. Based on the findings of this study and others, we recommend some key measures for all patients with a new diagnosis of KBG syndrome (summarized in Table II) to assist pediatric and other colleagues involved in the care of patients. Five of the patients were referred for investigation of possible craniosynostosis on the basis of the broad forehead and brachycephaly, but no evidence of fused cranial sutures was found. This study is the largest to date of patients with KBG syndrome. Two were embarking on college courses at the time of the study. For KBG, ES methodology revealed that a non‐specific ANKRD11‐related phenotype exists, as found for other conditions [Need et al., 2012]. People with KBG syndrome are more likely to KBG syndrome is caused by changes (mutations) in or a deletion of the ANKRD11 gene on chromosome 16 (band q24.3). We have therefore, devised a diagnostic aid for KBG syndrome (Fig. KBG syndrome was initially thought to be quite rare, however is likely underdiagnosed due to mild features [4]. To date, KBG syndrome has been reported in 45 patients. Learn more. In some cases, KBG syndrome is caused by a mutation in the ANKRD11 gene … Features include unusually large upper front teeth (macrodontia), wide, short skull (brachycephaly), widely spaced eyes (hypertelorism), and wide eyebrows that may grow together in the middle (synophrys). Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Across the literature, 99% of patients had learning difficulties (Fig. The high GC content of the ANKRD11 gene necessitated the use of a GC‐RICH (Roche) PCR system. A syndrome characterized by macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, and neurologic involvement that includes global developmental delay, seizures, and intellectual disability. One of our patients (13) has been treated with growth hormone and some success has been reported elsewhere [Reynaert et al., 2015]. Furthermore, despite consensus regarding the gestalt of KBG, our data demonstrate that the facial features can be very subtle or unrecognizable. KBG syndrome. KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. Some patients were described as having a low anger threshold and a few had severely challenging behavior such as tantrums, inconsolable upset, and occasional aggressive outbursts. Comparison of the phenotypes in patients 5–8 and 29–31 demonstrate intra‐familial variability and variable penetrance. The subtle facial features of KBG syndrome were recognizable in half the patients. 1i). Have a look at things that other people have done to be happy with KBG Syndrome World map of KBG Syndrome View more Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. Please check your email for instructions on resetting your password. To date (January 2016), in addition to those reported here, 14 further patients with a variant in ANKRD11 have been identified by the DDD study (32 intragenic SNV/indels and one intragenic deletion in the first 4294 trios). Eight of the cohort were aged 18 or over including a parent identified after his daughter was diagnosed. Characteristic facial features may include wide set eyes, telecanthus and brachycephaly. We established single gene analysis of ANKRD11 (TS) as a diagnostic test at Bristol Genetics Laboratory in 2014 for patients considered to have KBG syndrome. SEN, statement of education need; PVL, periventricular leukomalacia on MRI; ant, anterior; AF, anterior fontanelle; dn, de novo; DCF, delayed closure of fontanelle age >3y; EH, enamel hypoplasia; AF, anterior fontanelle; TM, tympanic membrane; SNHL(mat), sensorineural hearing loss (maternal history); SPC, single palmar crease. Similarly, a mother diagnosed after KBG syndrome was identified in her son through DDD, described mild learning difficulties but was living independently, working in a kitchen and looking after her family without support. Half the patients (17/32) had eye abnormalities, most commonly strabismus and refractive errors (Fig. A skeletal survey was available in six patients and three of these revealed significant but non‐specific radiological signs. 3) which does not rely on the original features‐this would have identified all but one (patient 22 who is notably atypical in his overgrowth parameters) in our cohort. The precise role of ANKRD11 in bone formation and modelling is also currently unknown. We then amalgamated our data with those previously published which enabled us to estimate the frequency of features in 100 patients (Fig. When we compared the facial phenotypes of patients in the two diagnostic pathways, we observed that in the targeted group the gestalt was present in a higher proportion of cases than in the DDD group, where it was only clear in three. DNA samples were collected as parent/child trios. Another had generalised ichthyosis and predominantly lower limb lymphoedema. 2011–. Each chapter in GeneReviews is written by one or more experts on the specific condition or disease and goes through a rigorous editing and peer review process before being published online. In no instances did patients lose skills or regress. KBG syndrome (OMIM #148050) is a rare, autosomal dominant inherited genetic disorder that is caused by heterozygous mutations in the ankyrin repeat domain-containing protein 11 (ANKRD11) gene (Sirmaci et al., 2011) or by microdeletion of chromosome 16q24.3 that includes the ANKRD11 gene (Willemsen et al., 2010; Isrie et al., 2012).The syndrome is characterized … We also identified palatal abnormalities/dysfunction in a quarter of patients, which may be missed without specialist assessment. GeneReviews currently comprises 795 chapters. Introduction. Abnormalities of the head and face (craniofacial dysmorphism) may also be present. A further seven reported recurrent middle ear infections without lasting hearing loss. 148050 - KBG SYNDROME; KBGS To ensure long-term funding for the OMIM project, we have diversified our revenue stream. GeneReviews is a registered trademark of the University of Washington, Seattle. Living with KBG Syndrome can be difficult, but you have to fight to try to be happy. Other problems included a sensory processing disorder, rocking and flicking of elastic bands, a very unusual phenotype of echolalia‐imitation of an American accent, and autistic‐type behavior. It is implicated in activation of transcription by interaction with p160 coactivator and nuclear receptor complex by recruiting histone deacetylases [Sirmaci et al., 2011]. KBG syndrome is characterized by macrodontia of upper central incisors, distinctive craniofacial features such as triangular face, prominent nasal bridge, thin upper lip and synophrys; skeletal findings including short stature, delayed bone age, and costovertebral anomalies; and developmental delay/intellectual disability sometimes associated with seizures and EEG abnormalities. This is consistent with our finding that the gestalt can be unclear and easily missed. Copyright © 1993-2021, University of Washington, Seattle. Five patients had a diagnosis of attention deficit hyperactivity disorder (ADHD) and three others had mild symptoms in this spectrum. If you do not receive an email within 10 minutes, your email address may not be registered, In our analysis of the clinical findings of KBG we initially considered our cohort separately. This site needs JavaScript to work properly. Genetic counseling and testing terms used in GeneReviews are hyperlinked to definitions in the GeneReviews Glossary. The first showed a copper‐beaten appearance of the skull with small anterior beaks on the vertebrae at the thoracolumbar junction. Clinical presentation is characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays []Point mutations, indels, and large deletions in ANKRD11 account for most but not in all cases [2,3,4] Clinical characteristics: KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors), characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip), short stature, developmental delay / intellectual … The additional novel mutations occurred in single patients. UniProtKB (1) Reviewed (1) Swiss-Prot. A fused metopic suture was reported in one patient. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. COVID-19 is an emerging, rapidly evolving situation. He reported slow educational progress at primary school and did not achieve qualifications but was living independently as a father of three with no external help. Permanent conductive hearing loss of varying degrees was reported in a quarter of patients (8/32), all of whom had a history of recurrent otitis media and/or tympanic membrane perforation treated with grommet insertion. These children had a history of developmental delay/intellectual disability with or without additional features. Comparison of the phenotypes of all reported cases of recurrent mutations did not highlight specific correlations, although we noted that none of the eight c.1903_1907del patients had hearing loss or severe otitis media which was common in the cohort overall. Two scans showed moderate enlargement of the cisterna magna with normal ventricles (one also showing atrophic changes). 1i). KBG syndrome is characterized by macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, and neurologic involvement that includes global developmental delay, seizures, and intellectual disability (summary by Sirmaci et al., 2011). The ES group of children had been recruited to the DDD study because no clinical diagnosis had been made (20 patients from 10 of the 23 UK Clinical Genetic Centers). Detailed phenotyping has provided data on the range of physical features in this condition including wide anterior fontanelle with delayed closure, not previously described. In 22% of patients, we found a wide anterior fontanelle with delayed closure and speculate this may contribute to the triangular face shape in KBG syndrome. Alamut software v2.3.1 (Interactive Biosoftware, Rouen, France) was used to predict the effect of genetic variation. Prevention and treatment information (HHS). and you may need to create a new Wiley Online Library account. One child had sleep apnea which persisted after adenotonsillectomy. of upper incisors in most of our patients (23/27 with secondary dentition) and 82% of patients with KBG syndrome overall (Fig. To ensure continuing relevant and medically actionable content, each GeneReviews chapter is updated every four to five years (or as needed) by the author(s) in a formal and comprehensive process curated by the GeneReviews editors. Genomic DNA was received from an external laboratory or isolated from peripheral blood leukocytes using a Gentra Puregene cell kit (QIAGEN Ltd). Washington (DC): Department of Veterans Affairs (US); 2011–. Enter your email address below and we will send you your username, If the address matches an existing account you will receive an email with instructions to retrieve your username, Facial, dental and limb features in KBG syndrome. Additional supporting information may be found in the online version of this article at the publisher's web‐site. 2020 Nov 23. All babies reached a gestation of at least 36 weeks and the vast majority were delivered at term. We report a clinical and molecular study of 39 patients affected by KBG syndrome. GeneReviews, an international point-of-care resource for busy clinicians, provides clinically relevant and medically actionable information for inherited conditions in a standardized journal-style format, covering diagnosis, management, and genetic counseling for patients and their families. Careers. Only four children had a movement disorder including one with Tourette‐like tics. The key dental findings in our study (Figs. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. Resource Materials include additional information on key genetics concepts used in GeneReviews. We may therefore have underestimated the frequency of palatal abnormalities. No, it is not a dyslexic russian spy syndrome, it is a syndrome tied to global cognitive delays, craniofacial anomalies and a variety of skeletal challenges. Evidence Brief: The Effectiveness Of Mandatory Computer-Based Trainings On Government Ethics, Workplace Harassment, Or Privacy And Information Security-Related Topics. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%.