Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Mar;80(3):617-625.
doi: 10.1016/j.jaad.2018.09.042. Epub 2018 Oct 2.

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

Evelyn Lilly  1 , Christopher G Bunick  2 , Alexander M Maley  3 , Shali Zhang  3 , Mary K Spraker  3 , Amy J Theos  4 , Karina L Vivar  5 , Lucia Seminario-Vidal  5 , Adam E Bennett  5 , Robert Sidbury  6 , Yasushi Ogawa  7 , Masashi Akiyama  7 , Barbara Binder  8 , Smail Hadj-Rabia  9 , Raffaella A Morotti  10 , Earl J Glusac  11 , Keith A Choate  11 , Gabriele Richard  12 , Leonard M Milstone  2
Affiliations

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

Evelyn Lilly et al. J Am Acad Dermatol. 2019 Mar.

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.

Keywords: connexin 26; gap junction protein, beta-2; keratitis, ichthyosis, and deafness syndrome.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: The authors have no conflict of interest to declare

Figures

Figure 1.
Figure 1.. Late skin findings in lethal KID syndrome.
Intertriginous hyperkeratosis and denudation in a patient with GJB2 p.A88V mutation (case 1).
Figure 2.
Figure 2.. Histopathology of skin and esophagus in lethal KID syndrome.
(a) Skin from thigh in Figure 1 shows hyperkeratosis, papillomatosis and focal ballooning degeneration, with pale cytoplasm in keratinocytes of the upper epidermis. (b). Distal esophagus from case 1 shows thin mucosa limited to basal layer with no maturation and hyperchromatic nuclei. (c). Disordered maturation in the few areas where the mucosa is not thin. (d) Matched normal control of distal esophagus from 2-month infant. Hematoxylin and Eosin. Bar = 100um.
Figure 3.
Figure 3.. Structural analysis of Cx26 containing the p.A88V mutation
. (a) A single Cx26 protomer (orange) with the transmembrane region of the second transmembrane helix (TM2) highlighted in blue. The critical P87 adjacent to A88 is shown in a zoomed-in image of the TM2 helix and illustrates helical kinking induced by P87 (green lines aid visualization of the altered helical angle). Also shown are the positions of external G45 (yellow sphere) far from the carbamate binding region, and internal R104 on TM2 (purple sphere) involved in carbamate binding. (b) Cx26 hemichannel (top) with zoomed-in image (bottom) of three neighboring Cx26 protomers (colored blue, orange, and tan) showing the R104 (purple) and K125 (green) residues critical to CO2 binding. The distance between these residues ranges from ~ 6.1 to 6.5 Å.
See this image and copyright information in PMC

References

    1. Gilliam A, Williams ML. Fatal septicemia in an infant with keratitis, ichthyosis, and deafness (KID) syndrome. Pediatr Dermatol 2002;19:232–6. - PubMed
    1. Koppelhus U, Tranebjaerg L, Esberg G, Ramsing M, Lodahl M, Rendtorff ND et al. A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis-ichthyosis-deafness (KID) syndrome. Clin Exp Dermatol 2011;36:142–8. - PubMed
    1. Ogawa Y, Takeichi T, Kono M, Hamajima N, Yamamoto T, Sugiura K et al. Revertant mutation releases confined lethal mutation, opening Pandora’s box: a novel genetic pathogenesis. PLoS Genet 2014;10:e1004276. - PMC - PubMed
    1. Jonard L, Feldmann D, Parsy C, Freitag S, Sinico M, Koval C et al. A familial case of Keratitis- Ichthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E. Eur J Med Genet 2008;51:35–43. - PubMed
    1. Sbidian E, Feldmann D, Bengoa J, Fraitag S, Abadie V, de Prost Y et al. Germline mosaicism in keratitis-ichthyosis-deafness syndrome: pre-natal diagnosis in a familial lethal form. Clin Genet 2010;77:587–92. - PubMed

MeSH terms

Supplementary concepts