G C A T T A C G G C A T genes Article Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants Involving the ANKRD11 Gene or Submicroscopic Chromosomal Rearrangements of 16q24.3 Anna Kutkowska-Ka´zmierczak 1,* , Maria Boczar 2, Ewa Kalka 3, Jennifer Castañeda 1, Jakub Klapecki 1, Aleksandra Pietrzyk 4, Artur Barczyk 1, Olga Malinowska 1, Aleksandra Landowska 1, Tomasz Gambin 1, Katarzyna Kowalczyk 1 , Barbara Wi´sniowiecka-Kowalnik 1, Marta Smyk 1, Mateusz Dawidziuk 1 , Katarzyna Niepokój 1 , Magdalena Paczkowska 1, Paweł Szyld 1, Beata Lipska-Zi˛etkiewicz 5,6, Krzysztof Szczałuba 7 , Ewa Kostyk 8, Agata Runge 9,10, Karolina Rutkowska 7 , Rafał Płoski 7 , Beata Nowakowska 1, Jerzy Bal 1, Ewa Obersztyn 1 and Monika Gos 1 1 Department of Medical Genetics, Institute of the Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland; [email protected] (J.C.); [email protected] (J.K.); [email protected] (A.B.); Citation: Kutkowska-Ka´zmierczak, [email protected] (O.M.); [email protected] (A.L.); A.; Boczar, M.; Kalka, E.; Castañeda, [email protected] (T.G.); [email protected] (K.K.); [email protected] (B.W.-K.); [email protected] (M.S.); J.; Klapecki, J.; Pietrzyk, A.; Barczyk, [email protected] (M.D.); [email protected] (K.N.); A.; Malinowska, O.; Landowska, A.; [email protected] (M.P.); [email protected] (P.S.); Gambin, T.; et al. Wide Fontanels, [email protected] (B.N.); [email protected] (J.B.); [email protected] (E.O.); Delayed Speech Development and [email protected] (M.G.) Hoarse Voice as Useful Signs in the 2 Pediatric Surgery Clinic, Institute of the Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland; Diagnosis of KBG Syndrome: A [email protected] Clinical Description of 23 Cases with 3 Unit of Anthropology, Institute of the Mother and Child, Kasprzaka 17a, 01-211 Warsaw, Poland; Pathogenic Variants Involving the [email protected] ANKRD11 Gene or Submicroscopic 4 Department of Clinical Genetics and Pathomorphology, University of Zielona Góra, Chromosomal Rearrangements of 65-417 Zielona Góra, Poland; [email protected] 5 16q24.3. Genes 2021, 12, 1257. Rare Diseases Centre, Medical University of Gda´nsk,80-210 Gda´nsk,Poland; [email protected] 6 https://doi.org/10.3390/genes12081257 Clinical Genetics Unit, Department of Biology and Medical Genetics, Faculty of Medicine, Medical University of Gda´nsk,80-210 Gda´nsk,Poland 7 Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland; Academic Editors: Livia Garavelli [email protected] (K.S.); [email protected] (K.R.); [email protected] (R.P.) and Stefano Giuseppe Caraffi 8 Genetic Counselling Unit Kostyk&Kruczek, 31-436 Kraków, Poland; [email protected] 9 Genetic Department, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University Received: 26 May 2021 of Toru´n,85-067 Bydgoszcz, Poland; [email protected] Accepted: 12 August 2021 10 Genetic Counselling Clinic, Antoni Jurasz University Hospital, 05-094 Bydgoszcz, Poland Published: 17 August 2021 * Correspondence: [email protected]; Tel.: +48-22-32-77-361 or +48-22-32-77-452 Publisher’s Note: MDPI stays neutral Abstract: KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by with regard to jurisdictional claims in short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed published maps and institutional affil- closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 iations. gene or a chromosomal rearrangement involving this gene. We hereby present clinical evaluations of 23 patients aged 4 months to 26 years manifesting clinical features of KBG syndrome. Mutation analysis in the patients was performed using panel or exome sequencing and array CGH. Besides possessing dysmorphic features typical of the KBG syndrome, nearly all patients had psychomotor Copyright: © 2021 by the authors. hyperactivity (86%), 81% had delayed speech, 61% had poor weight gain, 56% had delayed closure Licensee MDPI, Basel, Switzerland. of fontanel and 56% had a hoarse voice. Macrodontia and a height range of −1 SDs to −2 SDs were This article is an open access article noted in about half of the patients; only two patients presented with short stature below −3 SDs. The distributed under the terms and conditions of the Creative Commons fact that wide, delayed closing fontanels were observed in more than half of our patients with KBG Attribution (CC BY) license (https:// syndrome confirms the role of the ANKRD11 gene in skull formation and suture fusion. This clinical creativecommons.org/licenses/by/ feature could be key to the diagnosis of KBG syndrome, especially in young children. Hoarse voice is 4.0/). a previously undescribed phenotype of KBG syndrome and could further reinforce clinical diagnosis. Genes 2021, 12, 1257. https://doi.org/10.3390/genes12081257 https://www.mdpi.com/journal/genes Genes 2021, 12, 1257 2 of 15 Keywords: KBG syndrome; ANKRD11 gene; 16q24.3; dysmorphic syndrome; wide, delayed closing fontanels; hoarse voice; speech delay; psychomotor hyperactivity; short stature 1. Introduction KBG syndrome (MIM #148050) is a neurodevelopmental disorder characterized by short stature, macrodontia, developmental delay, behavioral problems such as psychomotor hyperactivity, velopharyngeal insufficiency causing feeding problems and speech delay, and skeletal anomalies presenting as delayed closing of fontanels. Currently, more than 160 patients have been described but only a few reports paid attention to less common features of KBG syndrome, with a prevalence of less than 30%, such as undescended testes, cardiac defects, ocular findings including high myopia, strabismus, cataracts, advanced puberty, skin and hair anomalies, juvenile idiopathic arthritis, oral frenula, tics, lipoma of corpus callosum, prominent and elongated coccyx [1–6]. Among the reported cases, wide anterior fontanel with delayed closure has been described only in 8 out of 44 examined patients (18.2%) [3,7]. Voice disturbances such as dysphonic voice were found in two patients described by Gnazzo et al. [6]. No patient with hoarse voice and low timbre has yet been described, although the term “dysphonic”, “hypernasal speech” and “speech disorders” can probably describe a similar voice change or abnormal phonation [3,4,6]. Most patients with KBG syndrome possess a pathogenic variant involving the ANKRD11 (ankyrin repeat domain-containing protein 11) gene, which was reported as a causative gene in 2011 [8]. Chromosomal rearrangements encompassing the ANKRD11 gene, mainly 16q24.3 deletion, cause a similar phenotype. In addition, clinical features typical of the KBG syndrome were also described in two siblings and their mildly affected mother, in whom an ANKRD11 intragenic duplication was identified [7,9–15]. Herein, we describe a detailed clinical presentation of KBG syndrome in 23 patients: 13 with a pathogenic single nucleotide variant (SNV) in the ANKRD11 gene and 10 with a 16q24 rearrangement encompassing the ANKRD11 gene (nine patients with a microdeletion and one with a microduplication). 2. Materials and Methods 2.1. Patients and Clinical Investigations All patients (23) were clinically examined and recruited by clinical geneticists. Most patients (17/23) were from a single genetic center—the Department of Medical Genetics in the Institute of Mother and Child in Warsaw—while 6 patients were from Genetic Departments in other major cities of Poland (Gda´nsk,Kraków, Bydgoszcz). All but two patients—who were Ukrainian—were of Polish origin. All of the patients’ parents gave their informed consent for their children to be included in the study and for the anonymous publication of the patients’ photographs (with or without full face exposure), film and voice recordings in a professional medical journal. The group of patients in the study consisted of 23 patients: 13 patients with a pathogenic SNV of the ANKRD11 gene and 10 patients with rearrangements of 16q24.3 involving the same gene—nine patients with a microdeletion and one with a microduplication. Anthropometric Studies of Children with KBG Syndrome Basic anthropometric examination was performed in the majority of patients. In 11 patients (3 girls and 8 boys) aged from 4 months old to 15 years old and diagnosed with KBG syndrome in the years 2016–2021, detailed anthropometric analysis was performed in the Anthropology Unit of the Institute of Mother and Child in Warsaw. Genes 2021, 12, 1257 3 of 15 The children were measured using the previously described and approved technique of Martin and Saller (1957) and using standardized anthropometric equipment [16,17]. Four basic somatic measurements were collected from every evaluated child included in the study: height (length in the case of neonates and small babies), weight, head circumference and chest circumference. BMI score was also calculated. Moreover, three basic head measurements were recorded in all children: length, width and circumference. An additional six cephalometric measurements were obtained from four boys. The definitions of all nine head measurements are as follows: (1) Head circumference—measured with a tape around the maximum circumference of the head, just above the brow ridges at the front and the most protruding portion of the back of the head (occiput). (2) Head length (g—op)—from front to back—the distance from the brow ridge (glabella) to the most distant point on the back of the head on the occipital bone (opisthocranion) measured with a spreading caliper. (3) Head width (eu—eu)—the greatest distance between the most lateral points at the height of the parietal bones (euryon—euryon) measured with a spreading caliper. (4) Face breadth (zy—zy)—the greatest distance between the even points located most laterally on the zygomatic arches (zygion—zygion) measured with a spreading caliper.