More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations - 11/02/19
, Christopher G. Bunick, MD, PhD b, Alexander M. Maley, MD c, Shali Zhang, MD c, Mary K. Spraker, MD c, Amy J. Theos, MD d, Karina L. Vivar, MD e, Lucia Seminario-Vidal, MD, PhD e, Adam E. Bennett, MD, PhD e, Robert Sidbury, MD f, Yasushi Ogawa, MD g, Masashi Akiyama, MD, PhD g, Barbara Binder, MD h, Smail Hadj-Rabia, MD, PhD i, Raffaella A. Morotti, MD j, Earl J. Glusac, MD b, j, Keith A. Choate, MD, PhD b, j, Gabriele Richard, PhD k, Leonard M. Milstone, MD bAbstract |
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.
Il testo completo di questo articolo è disponibile in PDF.Key words : connexin 26, gap junction protein, beta-2, keratitis, ichthyosis, and deafness syndrome
Mappa
| Supported in part by the Dermatology Foundation through a Career Development Award (to Dr Bunick), a National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Dermatology Training Grant to Yale T 32 AR007016 (to Drs Bunick and Lilly; principal investigator: Richard Edelson), and a National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases grant 5K08AR070290-02 (to Dr Bunick). |
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| Conflicts of interest: None disclosed. |
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| Drs Lilly and Bunick contributed equally to this work. |
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| Presented as a poster at the Society of Investigative Dermatology annual meeting, Portland, Oregon, April 26-29, 2017. |
Vol 80 - N° 3
P. 617-625 - marzo 2019 Ritorno al numero
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