Evelyn Lilly1, Christopher G Bunick2, Alexander M Maley3, Shali Zhang3, Mary K Spraker3, Amy J Theos4, Karina L Vivar5, Lucia Seminario-Vidal5, Adam E Bennett5, Robert Sidbury6, Yasushi Ogawa7, Masashi Akiyama7, Barbara Binder8, Smail Hadj-Rabia9, Raffaella A Morotti10, Earl J Glusac11, Keith A Choate11, Gabriele Richard12, Leonard M Milstone2. 1. Department of Dermatology at Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: elilly1@mgh.harvard.edu. 2. Department of Dermatology, Yale School of Medicine, New Haven, Connecticut. 3. Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia. 4. Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama. 5. Department of Dermatology and Cutaneous Surgery, University of South Florida, Tampa, Florida. 6. Division of Dermatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington. 7. Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 8. Department of Dermatology, Medical University of Graz, Graz, Austria. 9. Department of Dermatology, Reference Center for Genodermatoses and Rare Skin Diseases, INSERM U1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Universitary Hospital, Paris, France. 10. Department of Pathology, Yale School of Medicine, New Haven, Connecticut. 11. Department of Dermatology, Yale School of Medicine, New Haven, Connecticut; Department of Pathology, Yale School of Medicine, New Haven, Connecticut. 12. GeneDx, Gaithersburg, Maryland.
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.
BACKGROUND:Infantdeath 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 GJB2p.A88V and GJB2p.G45E. RESULTS:Infantdeath occurred in all patients with GJB2p.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 GJB2p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central carbon dioxide sensing of GJB2p.A88V. LIMITATIONS: This clinical review was retrospective. CONCLUSION:GJB2p.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.
Authors: J Mazereeuw-Hautier; E Bitoun; J Chevrant-Breton; S Y K Man; C Bodemer; C Prins; C Antille; J-H Saurat; D Atherton; J I Harper; D P Kelsell; A Hovnanian Journal: Br J Dermatol Date: 2007-03-23 Impact factor: 9.302
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