BACKGROUND The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. METHODS We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. RESULTS Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. CONCLUSIONS The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K–AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.)

Although cochlear implants improve the ability of profoundly deaf children to understand speech, critics claim that the published literature does not document even a single case of a child who has developed a linguistic system based on input from an implant. Thus, it is of clinical and scientific importance to determine whether cochlear implants facilitate the development of English language skills. The English language skills of prelingually deaf children with cochlear implants were measured before and after implantation. We found that the rate of language development after implantation exceeded that expected from unimplanted deaf children (p < .001) and was similar to that of children with normal hearing. Despite a large amount of individual variability, the best performers in the implanted group seem to be developing an oral linguistic system based largely on auditory input obtained from a cochlear implant.Most children who are born profoundly deaf or who become deaf before the age of 3 fall significantly behind their normal-hearing peers in their mastery of the surrounding oral language in its written, read, spoken, and signed forms. Studies of English achievement in this population document significant delays in all language domains (Davis, 1974;Geers, Kuehn, & Moog, 1981;Levitt, McGarr, & Geffner, 1987;Osberger, Moeller, Eccarius, Robbins, & Johnson, 1986). Lexical-semantic and syntactic-morphological abilities have been shown to be severely delayed regardless of whether the profoundly deaf children used oral communication (OC, which excludes the use of manual signs) or total communication (TC, the simultaneous use of oral and manual language). Numerous studies have found that profoundly prelingually deaf children lag in their English language abilities with respect to normal-hearing children. For example, a group of children was tested before and after a 3-year experimental instructional program designed to provide maximum academic achievement under ideal conditions (Moog & Geers, 1985). These children were deaf at birth or before their first birthday, received early amplification and instruction, and had at least average nonverbal intelligence. After training, despite a mean age of 9.92 years, their receptive and expressive language abilities (as tested with the Northwestern Syntax Screening Test, which samples a variety of syntactic English skills; Lee, 1971) were at the level of normal-hearing 4.5-to 6.3-year-olds. Delays in language development were also found in a large-scale study of Stanford Achievement Test Reading Comprehension scores in 8-to 18-year-old hearing-impaired students who received special services in schools throughout the United States. The study showed that by the time these students finished high school, their median reading comprehension levels were below those of average normal-hearing third graders (Allen, 1986 Until the early 1980s, there was no treatment that would allow profoundly deaf persons to improve their hearing so they could understand speech again. With the a...

DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology. Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9. All three residues mutated in DFNA9 are conserved in mouse and chicken Coch, and are found in a region containing four conserved cysteines with homology to a domain in factor C, a lipopolysaccharide-binding coagulation factor in Limulus polyphemus. COCH message, found at high levels in human cochlear and vestibular organs, occurs in the chicken inner ear in the regions of the auditory and vestibular nerve fibres, the neural and abneural limbs adjacent to the cochlear sensory epithelium and the stroma of the crista ampullaris of the vestibular labyrinth. These areas correspond to human inner ear structures which show histopathological findings of acidophilic ground substance in DFNA9 patients.

This study examined the effects of age at implantation on the development of communication abilities in children with early implantation. The 73 participants were prelingually deafened, received a cochlear implant before 5 years of age, and used current cochlear implant technology. The children were administered a battery of speech and language outcome measures before implantation and again at successive 6-month postimplant intervals. A mixed model analysis was used to examine the rate of growth in word recognition and language skills as a function of age at time of implantation. The results revealed significant improvements in communication skills over time. Spoken word recognition improved at a faster rate in the oral children with early implantation. However, the children who underwent implantation before 3 years of age had significantly faster rates of language development than did the children with later implantation. The oral children demonstrated more rapid gains in communication abilities than did the children who used total communication.

This study examined the development of visual attention in 5- to 13-year-olds who differed in their access to sound. Hearing children, deaf children with cochlear implants, and deaf children without implants participated in a task in which they were to respond to some visual signals and not others. The results of Experiment I indicated that the timing of developmental changes in visual selective attention was similar for all 3 groups, occurring around 8 years. The magnitude of age-related change differed among groups; hearing children and older deaf children using a cochlear implant reached higher levels of performance with age than did deaf children without enhanced access to sound. The results of Experiment 2 suggest that the developmental differences between deaf children with and without cochlear implants begin prior to 8 years and may be related to their use of environmental sounds to organize visual attention.

IMPORTANCE Children who receive a cochlear implant (CI) for early severe to profound sensorineural hearing loss may achieve age-appropriate spoken language skills not possible before implantation. Despite these advances, reduced access to auditory experience may have downstream effects on fundamental neurocognitive processes for some children with CIs. OBJECTIVE To determine the relative risk (RR) of clinically significant executive functioning deficits in children with CIs compared with children with normal hearing (NH). DESIGN, SETTING, AND PARTICIPANTS In this prospective, cross-sectional study, 73 children at a hospital-based clinic who received their CIs before 7 years of age and 78 children with NH, with average to above average mean nonverbal IQ scores, were recruited in 2 age groups: preschool age (age range, 3–5 years) and school age (age range, 7–17 years). No children presented with other developmental, cognitive, or neurologic diagnoses. INTERVENTIONS Parent-reported checklist measures of executive functioning were completed during psychological testing sessions. MAIN OUTCOMES AND MEASURES Estimates of the RR of clinically significant deficits in executive functioning (≥ 1 SDs above the mean) for children with CIs compared with children with NH were obtained based on 2 parent-reported child behavior checklists of everyday problems with executive functioning. RESULTS In most domains of executive functioning, children with CIs were at 2 to 5 times greater risk of clinically significant deficits compared with children with NH. The RRs for preschoolers and school-aged children, respectively, were greatest in the areas of comprehension and conceptual learning (RR [95% CI], 3.56 [1.71–7.43] and 6.25 [2.64–14.77]), factual memory ( 4.88 [1.58–15.07] and 5.47 [2.03–14.77]), attention (3.38 [1.03–11.04] and 3.13 [1.56–6.26]), sequential processing (11.25 [1.55–81.54] and 2.44 [1.24–4.76]), working memory (4.13 [1.30–13.06] and 3.64 [1.61–8.25] for one checklist and 1.77 [0.82–3.83] and 2.78 [1.18–6.51] for another checklist), and novel problem-solving (3.93 [1.50–10.34] and 3.13 [1.46–6.67]). No difference between the CI and NH samples was found for visual-spatial organization (2.63 [0.76–9.03] and 1.04 [0.45–2.40] on one checklist and 2.86 [0.98–8.39] for school-aged children on the other checklist). CONCLUSIONS AND RELEVANCE A large proportion of children with CIs are at risk for clinically significant deficits across multiple domains of executive functioning, a rate averaging 2 to 5 times that of children with NH for most domains. Screening for risk of executive functioning deficits should be a routine part of the clinical evaluation of all children with deafness and CIs.

Cochlear implants (CIs) process sounds electronically and then transmit electric stimulation to the cochlea of individuals with sensorineural deafness, restoring some sensation of auditory perception. Many congenitally deaf CI recipients achieve a high degree of accuracy in speech perception and develop near-normal language skills. Post-lingually deafened implant recipients often regain the ability to understand and use spoken language with or without the aid of visual input (i.e. lip reading). However, there is wide variation in individual outcomes following cochlear implantation, and some CI recipients never develop useable speech and oral language skills. The causes of this enormous variation in outcomes are only partly understood at the present time. The variables most strongly associated with language outcomes are age at implantation and mode of communication in rehabilitation. Thus, some of the more important factors determining success of cochlear implantation are broadly related to neural plasticity that appears to be transiently present in deaf individuals. In this article we review the expected outcomes of cochlear implantation, potential predictors of those outcomes, the basic science regarding critical and sensitive periods, and several new research directions in the field of cochlear implantation.

Word-learning skills were tested in normal-hearing 12- to 40-month-olds and in deaf 22- to 40-month-olds 12 to 18 months after cochlear implantation. Using the Intermodal Preferential Looking Paradigm (IPLP), children were tested for their ability to learn two novel-word/novel-object pairings. Normal-hearing children demonstrated learning on this task at approximately 18 months of age and older. For deaf children, performance on this task was significantly correlated with early auditory experience: Children whose cochlear implants were switched on by 14 months of age or who had relatively more hearing before implantation demonstrated learning in this task, but later implanted profoundly deaf children did not. Performance on this task also correlated with later measures of vocabulary size. Taken together, these findings suggest that early auditory experience facilitates word learning and that the IPLP may be useful for identifying children who may be at high risk for poor vocabulary development.