More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations

• Type of Material: Article
• Authors: Evelyn Lilly, Harvard Medical School; Christopher G. Bunick, Yale University; Alexander M. Maley, Emory University; Shali Zhang, Emory University; Mary Spraker, Emory University; Amy J. Theos, University of Alabama Birmingham; Karina L. Vivar, University of South Florida; Lucia Seminario-Vidal, University of South Florida; Adam E. Bennett, University of South Florida; Robert Sidbury, University of Washington; Yasushi Ogawa, Nagoya University; Masashi Akiyama, Nagoya University; Barbara Binder, Medical University of Graz; Smail Hadj-Rabia, Paris Descartes - Sorbonne Paris Cite University; Raffaella A. Morotti, Yale University; Earl J. Glusac, Yale University; Keith A. Choate, Yale University; Gabriele Richard, Yale University; Leonard M. Milstone, Yale University
• Language: English
• Date: 2019-03-01
• Publisher: MOSBY-ELSEVIER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 American Academy of Dermatology, Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaad.2018.09.042
• Title of Journal or Parent Work: JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
• Volume: 80
• Issue: 3
• Start Page: 617
• End Page: 625
• Grant/Funding Information: This work was supported in part by the Dermatology Foundation through a Career Development Award (to C.G.B.), an NIH/NIAMS Dermatology Training Grant to Yale T 32 AR007016 (to C.G.B. and E.L.; PI: Richard Edelson), and an NIH/NIAMS grant 5K08AR070290–02 (to C.G.B).
• Keywords: FORM; and deafness syndrome; CHILD; keratitis; KID SYNDROME; Dermatology; Science & Technology; beta-2; Life Sciences & Biomedicine; ichthyosis; connexin 26; MODEL; gap junction protein
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery

Abstract

Background: Infant death in keratitis-ichthyosis-deafness (KID) syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood. Objective: We sought to discover characteristics that account for poor outcomes in lethal KID syndrome. Methods: We collected 4 new cases and 9 previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E. Results: Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those 2 “lethal” mutations is likely multifactorial: during life all had ≥1 serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central carbon dioxide sensing of GJB2 p.A88V. Limitations: This clinical review was retrospective. Conclusion: GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electrophysiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All patients with KID syndrome may have subtle abnormalities beyond the eyes, ears, and skin. Early genotyping of KID syndrome births will inform prognostic discussion.