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More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations.
Journal of the American Academy of Dermatology ( IF 12.8 ) Pub Date : 2018-10-02 , DOI: 10.1016/j.jaad.2018.09.042
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
Affiliation  

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.

中文翻译:

不仅仅是角膜炎,鱼鳞病和耳聋:致命GJB2突变的多系统作用。

背景技术已知在角膜炎-鱼鳞病-耳聋(KID)综合征中婴儿死亡。尚不清楚其与特定基因型和病理生理学的关系。目的我们试图发现导致致命性KID综合征预后不良的特征。方法我们收集了4例新病例和9例先前报道的基因型KID致死综合症病例。我们对致命突变体GJB2 p.A88V和GJB2 p.G45E进行了新的分子建模。结果所有GJB2 p.G45E和p.A88V患者均发生婴儿死亡。与其他GJB2突变不同寻常。带有这2个“致命”突变的早期死亡可能是多因素的:一生中所有患者均≥1个严重感染;大多数人体重增加不佳,呼吸困难严重;许多还具有其他解剖异常。GJB2 p的结构建模。G45E未发现对盐桥的影响,该盐桥先前被预测是造成GJB2 p.A88V异常中央二氧化碳感应的原因。局限性该临床回顾是回顾性的。结论GJB2 p.G45E和p.A88V是唯一具有统一早期致死率的KID综合征突变。在致命的KID综合征中,GJB2的那些电生理学严重突变揭示了许多器官的异常。所有患有KID综合征的患者,除眼,耳和皮肤外,都可能有细微的异常。KID综合征出生的早期基因分型将为预后讨论提供信息。A88V是唯一与统一的早期致死率相关的KID综合征突变。在致命的KID综合征中,GJB2的那些电生理学严重突变揭示了许多器官的异常。所有患有KID综合征的患者,除眼,耳和皮肤外,都可能有细微的异常。KID综合征出生的早期基因分型将为预后讨论提供信息。A88V是唯一与统一的早期致死率相关的KID综合征突变。在致命的KID综合征中,GJB2的那些电生理学严重突变揭示了许多器官的异常。所有患有KID综合征的患者,除眼,耳和皮肤外,都可能有细微的异常。KID综合征出生的早期基因分型将为预后讨论提供信息。
更新日期:2018-10-02
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