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More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations - 11/02/19

Doi : 10.1016/j.jaad.2018.09.042 
Evelyn Lilly, MD a, , 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 b
a Department of Dermatology at Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 
b Department of Dermatology, Yale School of Medicine, New Haven, Connecticut 
c Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia 
d Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama 
f Division of Dermatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington 
g Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan 
h Department of Dermatology, Medical University of Graz, Graz, Austria 
i 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 
e Department of Dermatology and Cutaneous Surgery, University of South Florida, Tampa, Florida 
j Department of Pathology, Yale School of Medicine, New Haven, Connecticut 
k GeneDx, Gaithersburg, Maryland 

Correspondence to: Evelyn Lilly, MD, Department of Dermatology, Massachusetts General Hospital, 50 Staniford St, 2nd fl, Boston, MA 02114.Department of DermatologyMassachusetts General Hospital50 Staniford St2nd flBostonMA02114

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.

Le texte complet de cet article est disponible en PDF.

Key words : connexin 26, gap junction protein, beta-2, keratitis, ichthyosis, and deafness syndrome


Plan


 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).
 Conflicts of interest: None disclosed.
 Drs Lilly and Bunick contributed equally to this work.
 Presented as a poster at the Society of Investigative Dermatology annual meeting, Portland, Oregon, April 26-29, 2017.


© 2018  American Academy of Dermatology, Inc. Tous droits réservés.
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Vol 80 - N° 3

P. 617-625 - mars 2019 Retour au numéro
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