Primrose syndrome: Characterization of the phenotype in 42 patients

• Type of Material: Article
• Authors: Daniela Melis, Federico II University; Daniel Carvalho, SARAH Network of Rehabilitation Hospitals; Tina Barbaro-Dieber, Cooks Childrens Genetics; Alberto J. Espay, University of Cincinnati; Michael Gambello, Emory University; Blanca Gener, Hospital Universitario Cruces; Erica Gerkes, University of Groningen; Marrit M. Hitzert, University of Groningen; Hanne B. Hove, Copenhagen University Hospital; Sandra Jansen, Radboud University Nijmegen Medical Centre; Petr E. Jira, Jeroen Bosch Hospital; Katherine Lachlan, University Hospitals of Southampton NHS Trust; Leonie A. Menke, Amsterdam Universitair Medisch Centrum; Vinodh Narayanan, Translational Genomics Research Institute; Damara Ortiz, UPMC Childrens Hospital Pittsburgh; Eline Overwater, University of Amsterdam; Renata Posmyk, Podlaskie Medical Center; Keri Ramsey, Translational Genomics Research Institute; Alessandro Rossi, University of Naples Federico II; Renata Lazari Sandoval, University of Naples Federico II; Constance Stumpel, Maastricht University Medical Centre; Kyra E. Stuurman, Erasmus Medical Center; Viviana Cordeddu, National Center for Drug Research and Evaluation; Peter Turnpenny, Royal Devon Exeter Healthcare NHS; Pietro Strisciuglio, University of Naples Federico II; Marco Tartaglia, Osped Pediat Bambino Gesu; Sheela Unger, University of Lausanne; Todd Waters, North Florida Regional Medical Center Emergency Department HCA/University of Central Florida College of Medicine Consortium Florida USA.; Clare Turnbull, Institute of Cancer Research; Raoul C. Hennekam, Amsterdam Universitair Medisch Centrum
• Language: English
• Date: 2020-04-20
• Publisher: Wiley
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/cge.13749
• Title of Journal or Parent Work: Clinical Genetics
• Volume: 97
• Issue: 6
• Start Page: 890
• End Page: 901
• Grant/Funding Information: None declared
• Keywords: Differentiation; Finger protein ZBTB20; alpha-fetoprotein; Genetics & Heredity; Life Sciences & Biomedicine; Science & Technology; ZBTB20; ectopic calcifications; Abnormalities; overgrowth; Primrose syndrome; Cancer; Alpha; Mutations
• Research Categories: Biology, Neuroscience; Biology, Genetics; Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.