Partial deletion of ANKRD11 results in the KBG phenotype distinct from the 16q24.3 microdeletion syndrome

KBG syndrome (OMIM 148050) is a very rare genetic disorder characterized by macrodontia, distinctive craniofacial abnormalities, short stature, intellectual disability, skeletal, and neurologic involvement. Approximately 60 patients have been reported since it was first described in 1975. Recently mutations in ANKRD11 have been documented in patients with KBG syndrome, and it has been proposed that haploinsufficiency of ANKRD11 is the cause of this syndrome. In addition, copy number variation in the 16q24.3 region that includes ANKRD11 results in a variable phenotype that overlaps with KBG syndrome and also includes autism spectrum disorders and other dysmorphic facial features. In this report we present a 2½‐year‐old African American male with features highly suggestive of KBG syndrome. Genomic microarray identified an intragenic 154 kb deletion at 16q24.3 within ANKRD11. This child's mother was mosaic for the same deletion (present in approximately 38% of cells) and exhibited a milder phenotype including macrodontia, short stature and brachydactyly. This family provides additional evidence that ANKRD11 causes KBG syndrome, and the mild phenotype in the mosaic form suggests that KBG phenotypes might be dose dependent, differentiating it from the more variable 16q24.3 microdeletion syndrome. This family has additional features that might expand the phenotype of KBG syndrome. © 2013 Wiley Periodicals, Inc.     

Oral characteristics of a patient with Ekman-Westborg-Julin trait: a case history

This article presents the case of a Japanese woman who had Ekman-Westborg-Julin trait. She had general macrodontia with multituberculism, evagination of the premolar, single conical roots, shovel-shaped incisors, enamel hypoplasia, impacted tooth, dental crowding, and an open bite. The oral and general characteristics of this patient are described and include the histological and radiographic findings of the mandibular third molars. We suggest that the distinctive oral features with macrodontia of the permanent teeth, multituberculism, evagination, single conical roots, and impaction of the tooth could be defined as the Ekman-Westborg-Julin trait.     

A new X-linked multiple congenital anomalies/ mental retardation syndrome

We report on 2 boys, the sons of sisters, and their mother's brother who have a new, X-linked multiple congenital anomalies/mental retardation (MCA/MR) syndrome. The propositus was a 16-month-old caucasian male with 1)mental retardation, 2) congenital microcephaly, 3)postnatal growth deficiency, 4)ridged metopic suture with narrow bifrontal diameter, 5)upslanted palpebral fissures with persistent epicanthal folds, strabismus, and lacrimal duct obstruction, 6)narrow palate, 7)macrodontia, 8)anteverted ears, 9)atrial septal defect, 10)dry brittle scalp hair and 11)cutis marmorata. His chromosomes were normal. His cousin and uncle were similarly affected. This distinctive MCA/MR syndrome is added to the list of X-linked malformation syndromes known at the present time.     

KBG syndrome: Common and uncommon clinical features based on 31 new patients

KBG syndrome (MIM #148050) is an autosomal dominant disorder characterized by developmental delay, intellectual disability, distinct craniofacial anomalies, macrodontia of permanent upper central incisors, skeletal abnormalities, and short stature. This study describes clinical features of 28 patients, confirmed by molecular testing of ANKRD11 gene, and three patients with 16q24 deletion encompassing ANKRD11 gene, diagnosed in a single center. Common clinical features are reported, together with uncommon findings, clinical expression in the first years of age, distinctive associations, and familial recurrences. Unusual manifestations emerging from present series include juvenile idiopathic arthritis, dysfunctional dysphonia, multiple dental agenesis, idiopathic precocious telarche, oral frenula, motor tics, and lipoma of corpus callosum, pilomatrixoma, and endothelial corneal polymorphic dystrophy. Facial clinical markers suggesting KBG syndrome before 6 years of age include ocular and mouth conformation, wide eyebrows, synophrys, long black eyelashes, long philtrum, thin upper lip. General clinical symptoms leading to early genetic evaluation include developmental delay, congenital malformations, hearing anomalies, and feeding difficulties. It is likely that atypical clinical presentation and overlapping features in patients with multiple variants are responsible for underdiagnosis in KBG syndrome. Improved knowledge of common and atypical features of this disorder improves clinical management.     

Root canal therapy of an anomalous maxillary central incisor: a case report

Abstract A case of endodontic conservative treatment of a maxillary central incisor with an atypical crown and Type III dens invaginatus is presented. The greatest difficulty was to locate the root canals due to the atypical internal anatomy. There were not two clear canals, but the coronal pulp chamber showed two entrances to the root canal. The tooth presented a distal periodontal pocket and various lingual radicular grooves. The appearance of the crown was improved by alteration of its dimension using diamond rotary instruments and correction with photopolymerized resin.     

KBG syndrome in two patients from Egypt

KBG syndrome is an intellectual disability (ID) associated with multiple congenital anomalies in which the macrodontia could be the clue for the diagnosis. It is caused either by heterozygous variant in ANKRD11 gene or 16q24.3 microdeletions that involve the ANKRD11 gene. Here, we report on two unrelated male patients who presented with ID, short stature, webbing of neck, and cryptorchidism. Noonan syndrome was suspected first but the presence of macrodontia in both patients pointed to KBG syndrome which was confirmed thereafter by the identification of a novel pathogenic variant in ANKRD11 gene, c.5488G>T (p.E1830*). Macrodontia was noticed in all the deciduous anterior teeth in Patient 1. This observation was reported previously in few patients, but it seems to be a common feature that could be misdiagnosed as premature eruption of teeth. Therefore, our results confirm that maxillary permanent central incisors may not be the only teeth affected in KBG but also all the deciduous teeth. Interestingly, desquamative gingivitis was additionally noted in Patient 1, which has not been reported previously, however; it could be a coincidental finding. To the best of our knowledge, this is the first report from Egypt.     

Clinical and genetic aspects of KBG syndrome

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat‐containing cofactors. We describe 32 KBG patients aged 2–47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype–genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. 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. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

     

Isolated soft tissue cleft lip: epidemiology and associated dental anomalies

Oral Diseases (2011) 17 , 221–231 Objectives: The aim of this investigation was to study the epidemiology of the isolated soft tissue cleft lip (ICL) population and to evaluate the dental anomalies associated with permanent dentition. Methods: The study included 19 children aged 9–13 years presenting ICL selected from 657 cleft lip‐affected patients treated during the last 10 years in two craniofacial centers. Only 17 patients could be included for dental anomaly evaluation: Hyperdontia, Hypodontia, Gemination, Talon tooth, Microdontia, and Macrodontia. These were compared with cleft lip and palate (CLP) and cleft lip and alveolus (CLA)‐affected populations and with normal populations. Results: The prevalence of ICL was 2.8%. All types of tooth abnormalities were found to be higher and mainly significant for the cleft side of ICL compared with the normal population. On the side opposite the cleft, the prevalence of dental anomalies reduced toward the normal individuals and was not significantly different. The significant differences found between CLP, CLA, and ICL‐affected populations were mostly depicted by lateral incisors and second pre‐molar hypodontia. Conclusions: Isolated cleft lip is a rare phenomenon among the spectrum of the cleft‐affected population. The prevalence of the dental anomalies in ICL maintains the proportional trend according to clefting severity.