Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy The 11p15.5 chromosomal region: When did the instability occur? Michael Shterenshis a, ⁎ , Yulia Roitblat b , Jacob Ilani c , Jeanne Lumbroso d , Nicolas Padilla-Raygoza e a Department of Anatomy, Alexander Muss High School in Israel (AMHSI) Affiliated with Alexander Muss Institute for Israel Education (AMIIE), Hod HaSharon, Israel b Department of Sciences, Belkind School for Special Education, Rishon-LeZion, Israel c Department of Anatomy, The Einstein Academy, Elgin, IL, USA d French Department, Alexander Muss High School in Israel (AMHSI) Affiliated with Alexander Muss Institute for Israel Education (AMIIE), Hod HaSharon, Israel e Department of Nursing and Obstetrics, Division of Health Sciences and Engineering, Campus Celaya-Salvatierra University of Guanajuato, Mexico ARTICLE INFO Keywords: 11p15.5 chromosomal region Idiopathic hemihyperplasia Lateral body overgrowth Beckwith-Wiedemann syndrome Russell-Silver syndrome Wilms tumor IMAGe syndrome ABSTRACT The disturbances of the 11p15.5 chromosomal region are associated with Beckwith-Wiedemann syndrome, Russell-Silver syndrome, Wilms tumor, IMAGe syndrome, and idiopathic hemihyperplasia. The aim of this re- search was to examine the hypothesis that 11p15.5 initially became unstable in the European population about 200 years ago. The medical literature from 1557 onwards, especially treatises on teratology, body asymmetry, and books of normal and pathologic anatomy, was searched for any mentioning of lateral body asymmetry, macroglossia and other possible visually detectable symptoms associated with the above-mentioned syndromes. The results indicate that lateral body asymmetry was not described before the first half of the 19th century, it was mentioned in the 1820s, and the first description of a true case was published in 1850. All first cases of hemihyperplasia were reported in continental Europe. Historical data suggest that the 11p15.5 chromosomal region became unstable in the first half of the 19th century. Our preliminary hypothesis is that de novo mutation occurred in continental Europe. Additional genetic research is needed to investigate the development of 11p15.5 instability during this period. Introduction IMAGe syndrome was described in 1999 [1]. Beckwith-Wiedemann syndrome was described in the 1960s [2]. Russell-Silver syndrome was described in the 1950s [3]. Wilms tumor was described in 1872 as nephroblastoma and became known as Wilms tumor after 1899 [4]. Idiopathic hemihyperplasia (IH) (congenital hemihypertrophy, hemi- gigantism, lateralized overgrowth) was described sometime in the first half of the 19th century that will be analyzed below. All these disorders are associated with disturbances of the 11p15.5 chromosomal region [5]. Lateral body asymmetry (LBA) can present itself either as hemi- hyperplasia (IH and Beckwith-Wiedemann syndrome) or as hemi- hypoplasia (IMAGe syndrome and Russell-Silver syndrome). It does not require surgical intervention, biopsy, X-Rays, MRI, molecular analysis, and genetic counseling for diagnosis. The diagnosis is made by ob- servation of a patient (Fig. 1). The question arises why LBA was over- looked for centuries of development of medical science? Three cen- turies is a period extremely short in the context of human genome evolution and extremely long in the context of the evolution of medical publishing and case reporting. Therefore, the subsequent question arises was LBA really overlooked? In addition to LBA, macroglossia may be a specific symptom of Beckwith-Wiedemann syndrome (syndromic patients) in association with the external ear abnormalities or can present itself as an isolated congenital abnormality (nonsyndromic patients). Macroglossia also can be a component of various other ge- netic syndromes, or of secondary origin (swollen tongue, tumor, neu- rofibromatosis, etc.). Genital abnormalities in males are specific for IMAGe syndrome. All such symptoms are detectable by observation and do not require any modern instrumental or imaging medical diagnostic tools. Were they also overlooked? The hypothesis The aim of this research was to confirm or to disprove the hy- pothesis that the instability of the 11p15.5 chromosomal region oc- curred in the first half of the 19th century and that the event took place in continental Europe. The age of the mutation that leads to LBA and IH is not calculated yet. In fact, while several genes of the 11p15.5 chro- mosomal region may be involved at the same time (including WT2 gene for Wilms tumor) thus producing various above-mentioned syndromes, it is appropriate to speak of general instability of the region. For ge- netics, the precise knowledge of when the 11p15.5 region became https://doi.org/10.1016/j.mehy.2018.09.008 Received 14 July 2018; Accepted 5 September 2018 ⁎ Corresponding author at: Aliyat HaNoar 9, Hod HaSharon 45102, Israel. E-mail address: mshterenshis@amhsi.org (M. Shterenshis). Medical Hypotheses 121 (2018) 21–25 0306-9877/ © 2018 Elsevier Ltd. All rights reserved. T