Valganciclovir in Infants with Hearing Loss and Clinically Inapparent Congenital Cytomegalovirus Infection: A Nonrandomized Controlled Trial.

OBJECTIVE: To assess the efficacy of valganciclovir in infants with hearing loss and clinically inapparent congenital cytomegalovirus infection (cCMV), as there is no consensus on treatment of this group. STUDY DESIGN: A nationwide, nonrandomized controlled trial, comparing 6 weeks of oral valganciclovir to no treatment in infants with cCMV, recruited after newborn hearing screening resulted in referral to an audiologist. The choice whether to treat was left to parents of subjects. Eligible subjects were full term infants aged <13 weeks with sensorineural hearing loss and diagnosed with cCMV through dried blood spot testing. The primary outcome, measured by linear and ordinal logistic regression, was change in best-ear hearing from baseline to follow-up at 18-22 months of age. RESULTS: Thirty-seven participants were included in the final analysis, of whom 25 were in the treatment group and 12 in the control group. The majority of subjects in both groups had neuroimaging abnormalities, which were mostly mild. Hearing deterioration was more likely in the control group compared with the treatment group (common OR 0.10, 95% CI 0.02-0.45, P = .003). Mean best-ear hearing deteriorated by 13.7 dB in the control group, compared with improvement of 3.3 dB in the treatment group (difference 17 dB, 95% CI 2.6 - 31.4, P = .02). CONCLUSIONS: We investigated treatment in children with hearing loss and clinically inapparent cCMV. Although our study was nonrandomized, it is the first prospective and controlled trial in this population. Valganciclovir-treated children with hearing loss and inapparent cCMV had less hearing deterioration at 18 through 22 months of age than control subjects. EUDRACT REGISTRY NUMBER: 2013-003068-30.

Concise tool based on language milestones identifies children with specific language impairment at 24-45 months of age.

AIM: This study aimed to develop a concise tool with acceptable predictive properties to identify young children with specific language impairment (SLI). METHODS: In this nested case-control study children with SLI attending two special needs schools for severe speech and language difficulties in the Netherlands were matched by date of birth and sex with control children attending mainstream education. This study analysed the predictive validity for having SLI at a mean age of eight years and three months (range 4-11 years) using combinations of six language milestones that were registered at 24, 36 and 45 months and retrieved from the children's healthcare files in 2012. RESULTS: We included 253 pairs of children with and without SLI. During a single visit, combinations of two milestones at one age achieved a specificity of at least 97% and sensitivities ranged from 32% to 64%. However, the concise tool, which combined five milestones at three different ages - 24, 36 and 45 months - had a specificity of 96% (95% confidence interval 94-99%) and a sensitivity of 71% (95% confidence interval 66-77%). CONCLUSION: Combining milestones at different ages provided a concise tool that could help to detect children with SLI at a young age.

Children with specific language impairment are more likely to reach motor milestones late.

BACKGROUND: Delayed language development without an obvious cause is considered an isolated developmental disorder and is called specific language impairment (SLI). SLI is probably the most prevalent developmental disorder in childhood with a generally cited prevalence of 7%. This study aimed to investigate whether SLI is always an isolated disorder or if children with SLI also have delayed motor development. METHODS: We used data of an earlier study with a prospective nested case-control design in which developmental data were collected from child health care files. Cases were children (4-11 years) with diagnosed SLI. They were matched by sex and date of birth with control children attending mainstream education. Data of both groups on seven gross and six fine motor milestones which had been registered in the Dutch Developmental Instrument between the ages of 15-36 months were retrieved from child health care files. McNemar tests were performed to test for differences in reaching motor milestones at the age norm between the case and control group. RESULTS: Data from 253 children in each group were available. A significant difference was found between both groups in the proportion failing to reach three of the seven investigated gross motor milestones at the age norm (p < 0.05). The proportion of children not reaching the motor milestone at the age norm was significantly higher for five of the six fine motor milestones in children with SLI compared with control children (p < 0.05). CONCLUSIONS: More children with SLI are late in reaching motor milestones than children without SLI. This means that it is debatable whether SLI can be regarded as a "specific" impairment, which is not associated with other developmental problems. A broader developmental assessment is therefore indicated when diagnosing SLI.

Can You Hear What I Think? Theory of Mind in Young Children With Moderate Hearing Loss.

OBJECTIVES: The first aim of this study was to examine various aspects of Theory of Mind (ToM) development in young children with moderate hearing loss (MHL) compared with hearing peers. The second aim was to examine the relation between language abilities and ToM in both groups. The third aim was to compare the sequence of ToM development between children with MHL and hearing peers. DESIGN: Forty-four children between 3 and 5 years old with MHL (35 to 70 dB HL) who preferred to use spoken language were identified from a nationwide study on hearing loss in young children. These children were compared with 101 hearing peers. Children were observed during several tasks to measure intention understanding, the acknowledgement of the other's desires, and belief understanding. Parents completed two scales of the child development inventory to assess expressive language and language comprehension in all participants. Objective language test scores were available from the medical files of children with MHL. RESULTS: Children with MHL showed comparable levels of intention understanding but lower levels of both desire and belief understanding than hearing peers. Parents reported lower language abilities in children with MHL compared with hearing peers. Yet, the language levels of children with MHL were within the average range compared with test normative samples. A stronger relation between language and ToM was found in the hearing children than in children with MHL. The expected developmental sequence of ToM skills was divergent in approximately one-fourth of children with MHL, when compared with hearing children. CONCLUSION: Children with MHL have more difficulty in their ToM reasoning than hearing peers, despite the fact that their language abilities lie within the average range compared with test normative samples.

Long-term impairment attributable to congenital cytomegalovirus infection: a retrospective cohort study.

AIM: This study aimed to estimate long-term impairment attributable to congenital cytomegalovirus infection (cCMV). METHOD: This nationwide cohort study retrospectively assessed cCMV in children born in 2008 in the Netherlands, testing 31 484 stored neonatal dried blood spots. Extensive medical data of cCMV-positive children (n=133) and matched cCMV-negative comparison children (n=274) up to 6 years of age were analysed. RESULTS: Moderate to severe long-term impairment was diagnosed in 24.8% (33 out of 133) of all cCMV-positive children (53.8% in symptomatic, 17.8% in asymptomatic), compared with 12.0% (33 out of 274) of cCMV-negative children. Sensorineural hearing loss was seen only in five cCMV-positive children (3.8%). Developmental delays were diagnosed more often in cCMV-positive children than cCMV-negative children: motor (12.0% vs 1.5%), cognitive (6.0% vs 1.1%), and speech-language (16.5% vs 7.3%). Long-term impairment in multiple domains was more frequent in symptomatic (19.2%) and asymptomatic (8.4%) cCMV-positive children than cCMV-negative children (1.8%). INTERPRETATION: Children with cCMV were twice as likely to have long-term impairment up to the age of 6 years, especially developmental delays and sensorineural hearing loss, than cCMV-negative comparison children, with a risk difference of 12.8%. These insights into the risk of cCMV-associated impairment can help optimize care and stimulate preventive measures. WHAT THIS PAPER ADDS: Congenital cytomegalovirus infection (cCMV) leads to impairment in 25% of cases. Fifty per cent of children with cCMV symptoms at birth have long-term impairment. The risk difference of moderate to severe long-term impairment between children with and without cCMV is 13%, attributable to cCMV. cCMV leads to motor, cognitive, and speech-language developmental delay in children.

Failure to meet language milestones at two years of age is predictive of specific language impairment.

AIM: This study established predictive properties of single language milestones for specific language impairment (SLI) after the age of four, as these had not previously been reported in the literature. METHODS: In this nested case-control study, children attending special needs schools for severe speech and language difficulties were matched with children attending mainstream schools. Data covering the ages of zero to four years were retrieved from well-child care clinics and the outcomes of 23 language milestones in the Dutch Developmental Instrument were analysed. The predictive properties were expressed as positive likelihood ratios, sensitivity and specificity. RESULTS: We included 253 pairs of children with and without SLI, aged from four to 11 years. The mean age was eight years and three months, and 77% were boys. From the age of 18 months, cases and controls differed significantly on all milestones (p < 0.01). After 24 months, the language milestones had positive likelihood ratios that ranging from 6 to 108. In general, language milestones had a high specificity (range 77-100%), but the sensitivity was relatively low (range 0-68%). CONCLUSION: Failure to meet language milestones from the age of 24 months was predictive of SLI, but the use of separate milestones had limited value due to low sensitivity.

Missed cases in the detection of child abuse based on parental characteristics in the emergency department (the Hague Protocol).

INTRODUCTION: We aimed to assess the number of "missed cases" in the detection of child abuse based on the Hague Protocol. This protocol considers 3 parental characteristics of ED adult patients to identify child abuse: (1) domestic violence, (2) intoxication, and (3) suicide attempt or auto-mutilation. METHODS: This study focuses on parents whose children should have been referred to the Reporting Centre for Child Abuse and Neglect (RCCAN) in the Hague, the Netherlands, according to the guidelines of the Hague Protocol. Data were collected from all referrals by the Medical Centre Haaglanden (Medisch Centrum Haaglanden) to the RCCAN in the Hague between July 1 and December 31, 2011. The hospital's database was searched to determine whether the parents had visited the emergency department in the 12 months before their child's referral to the RCCAN. RESULTS: Eight missed cases out of 120 cases were found. The reasons for not referring were as follows: forgetting to ask about children and assuming that it was not necessary to refer children if parents indicated that they were already receiving some form of family support. DISCUSSION: Barriers to identifying missing cases could be relatively easy to overcome. Regular training of emergency nurses and an automated alert in the electronic health record to prompt clinicians and emergency nurses may help prevent cases being missed in the future.

Problem behavior of individuals with Down syndrome in a nationwide cohort assessed in late adolescence.

OBJECTIVE: To assess problem behavior in adolescents with Down syndrome and examine the association with sex and severity of intellectual disability. STUDY DESIGN: Cross-sectional data of a Dutch nationwide cohort of Down syndrome children aged 16-19 years were collected using a written parental questionnaire. Problem behavior was measured using the Child Behavior Checklist and compared with normative data. The degree of intellectual disability was determined using the Dutch Social competence rating scale. RESULTS: The response rate was 62.8% (322/513), and the mean age 18.3 years (SD ± 0.8). The total score for problem behavior was higher in adolescents with Down syndrome than in adolescents without Down syndrome (26.8 vs 16.5; P < .001). Overall, 51% of adolescents with Down syndrome had problem scores in the clinical or borderline range on 1 or more Child Behavior Checklist subscales; this is more than twice as high as adolescents without Down syndrome. Adolescents with Down syndrome had more internalizing problems than their counterparts without Down syndrome (14% and 9%, respectively, in the clinical range); the percentages for externalizing problems were almost equal (7% and 9%, respectively, in the clinical range). The highest problem scores in adolescents with Down syndrome were observed on the social problems and thought problems subscales (large to very large standardized differences). Male sex and/or more severe mental disabilities were associated with more behavioral problems. CONCLUSIONS: Serious problem behavior is more prevalent in adolescents with Down syndrome. This demonstrates the need for a focus on general behavior improvement and on the detection and treatment of specific psychopathology in individuals with Down syndrome.

Targeted screening for congenital cytomegalovirus infection: clinical, audiological and neuroimaging findings.

OBJECTIVE: To evaluate clinical, audiological and neuroimaging findings in a cohort of infants diagnosed with congenital cytomegalovirus (cCMV) infection after failure at newborn hearing screening. METHODS: A prospective observational study in the Netherlands, using the existing newborn hearing screening infrastructure for well babies. Between July 2012 and November 2016, cytomegalovirus (CMV) PCR testing of neonatally obtained dried blood spots (DBS) was offered to all infants who failed newborn hearing screening. Clinical, neuroimaging and audiological data were collected. RESULTS: DBS of 1374 infants were successfully tested and 59 were positive for CMV (4.3%). Data of 54 infants were retrieved. Three were small for gestational age and six had microcephaly. Forty-eight (89%) had sensorineural hearing loss (SNHL), of whom half had unilateral SNHL. In both unilaterally and bilaterally affected children, the majority of the impaired ears had severe or profound hearing loss. Neuroimaging abnormalities were found in 40 of 48 (83%) children who had evaluable cranial ultrasound and/or cerebral MRI. The abnormalities were mild in 34, moderate in 3 and severe in 3 infants. The degree of SNHL and the severity of neuroimaging abnormalities were found to be correlated (p=0.002). CONCLUSIONS: The yield of targeted cCMV screening following newborn hearing screening failure was eight times higher than the estimated national birth prevalence of cCMV. The majority of this cohort of infants with clinically unsuspected cCMV disease had confirmed SNHL, neuroimaging abnormalities and lower than average birth weights and head circumferences. Newborns who fail newborn hearing screening should be tested for CMV to ensure appropriate clinical, neurodevelopmental and audiological follow-up.

Clinical practice: The approach to the deaf or hard-of-hearing paediatric patient.

Approximately 1 child in 1,000 is deaf or severely hard of hearing from birth, and the prevalence rises to about 1.6 per 1,000 in adolescents. Providing medical care for this group of children poses special challenges for professionals. To allow a medical consultation to proceed successfully and to the satisfaction of the patient, it is essential that physicians are aware of the different linguistic and cultural background of these patients. Healthcare workers should be aware of the possible higher incidence of comorbidities, sexual abuse and (psycho)social problems, of the possible pitfalls in obtaining informed consent and higher frequency of medical mistakes. This review describes the communication challenges and medical, ethical and legal issues a physician can experience when faced with these patients.

ESPGHAN's 2008 recommendation for early introduction of complementary foods: how good is the evidence?

Since 2002, the World Health Organization and many governments and professional associations have recommended exclusive breastfeeding for 6 months followed by complementary feeding (giving solid foods alongside breast milk) as optimal infant feeding practice. Several articles have been published challenging this recommendation. Arguably, the most influential has been the 2008 commentary of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition, which recommended that complementary foods should be introduced to all infants between 17 and 26 weeks. We challenge the validity of ESPGHAN's position, questioning the adequacy of the literature search, the interpretation and evidence used to reach their conclusions and the balance of an approach that focuses on disease prevention, with scant consideration of growth and neuromotor development. We contend that ESPGHAN's position should be understood as an expert opinion that may be influenced by conflicts of interest. In our view, the ESPGHAN position paper is not evidence based and does not justify a change of the current public health recommendation for 6 months of exclusive breastfeeding. At an individual level, health professionals should understand that developmental readiness for starting solid foods has an age range like other developmental milestones; that fewer infants will probably be ready to start complementary feeding before, rather than after, 6 months; and that their role is to equip parents with the confidence and skills to recognise the signs of developmental readiness. This empowerment process for infants and parents should be preferred over the prescriptive ESPGHAN approach.

Specialized outpatient clinic for deaf and hard-of-hearing patients in the Netherlands: Lessons learned in an attempt to improve health care.

RATIONALE, AIMS, AND OBJECTIVE: A group of organizations and individuals in the Netherlands collaborated to attempt to improve access to health care and health education for deaf and hard of hearing (DHH) patients in the country. The outcome was the start of a specialized outpatient clinic named PoliDOSH. An independent research group was set up to evaluate the effect of this specialized clinic. Even though the initiative did not succeed and was closed after 2 years, an extensive analysis of the start-up and functioning of the whole process was made. METHODS: Structured and nonstructured questionnaires and structured interviews. RESULTS: Only a small group of DHH patients indicated that they felt a need for consultations at the PoliDOSH. It became clear that to ensure successful functioning of a specialized facility the team members should include a representative group of DHH members. All key functions should be filled by top experts in the relevant fields as well as an expert in communication and needs of the target group. CONCLUSIONS: There is a great need for facilities to collect and disseminate information to and about DHH patients. The information should be aimed at providing psycho-education for the DHH persons themselves and health care professionals, concerning the specific needs and problems of this patient group. If a similar facility is set up in the future, thorough market research prior to start up is needed to enable the facility to connect with the needs of patients. The start-up period should allow sufficient time for the project to become known and for patients to become familiar with it and trust it.

Quality of life of children with hearing loss in special and mainstream education: A longitudinal study.

OBJECTIVES: To compare the quality of life (QoL) of children with hearing loss (HL) and children with normal hearing (NH) and to examine how the QoL of children with HL changes over time, considering language skills, type of hearing device, degree of HL, and type of education. METHODS AND MATERIALS: This longitudinal study included 62 children with HL and their parents. Developmental outcome data were collected at two time points, when the mean ages of the children were 4 and 11 years. The Pediatric Quality of Life (PedsQL™) questionnaire, which includes assessments of Physical, Emotional, Social, and School functioning, was completed by parents at both time points and by the children with HL at the second time point. Receptive and expressive language skills at 4 years were assessed by the Reynell Developmental Language Scale. Results were compared with a Dutch normative sample. RESULTS: The QoL of children with HL was similar to that of children with NH at both time points on two of the four QoL scales, Emotional and Physical functioning. On the other two scales, Social and School functioning, children with HL who attended special education and children who switched to mainstream education showed lower scores than children with HL who were consistently in mainstream education and lower scores than children with NH. The School QoL of children with HL decreased over time, as did the School QoL of children with NH. Social QoL of children with cochlear implants decreased over time, but this was not the case in children with hearing aids. Language skills and the degree of HL did not clinically improve the QoL over time of preschool children with HL. CONCLUSIONS: The QoL of children with HL in mainstream education and the Physical and Emotional QoL of all children with HL were satisfactory. It is essential to develop specific guidance regarding school activities for children with HL in special education and for children with HL who switch to mainstream education in order to increase their social QoL.

Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations.

Craniosynostosis, the premature fusion of one or more cranial sutures, is a developmental defect that disrupts the cranial morphogenetic program, leading to variable dysmorphic craniofacial features and associated functional abnormalities. Craniosynostosis is frequently observed as an associated feature in a number of clinically and genetically heterogeneous syndromic conditions, including a group of disorders caused by activating mutations in genes coding for the fibroblast growth factor receptor family members FGFR1, FGFR2, and FGFR3. In these disorders, dysregulation of intracellular signaling promoted by the aberrant FGFR function is mediated, at least in part, by the RAS-MAPK transduction pathway. Mutations in KRAS, HRAS, and other genes coding for proteins participating in this signaling cascade have recently been identified as underlying Noonan syndrome (NS) and related disorders. While cardinal features of these syndromes include distinctive dysmorphic facial features, reduced growth, congenital heart defects, and variable ectodermal anomalies and cognitive impairment, craniosynostosis is not a recognized feature. Here, we report on the occurrence of premature closure of cranial sutures in subjects with NS, and their specific association with mutations in the KRAS gene. These findings highlight the pathogenetic significance of aberrant signaling mediated by the RAS signaling pathway in other known forms of craniosynostosis, and suggest that, even in the absence of radiologically demonstrable synostosis of the calvarian sutures, dysregulated growth and/or suture closure at specific craniofacial sites might contribute to the craniofacial anomalies occurring in NS.

An implementation study of neonatal hearing screening in the Netherlands.

The objective of this study was to investigate whether universal neonatal hearing screening could be integrated in the youth health care program. The screening was performed by nurses of the well baby clinics. A three stage transient evoked otoacoustic emission screening was performed in three different screening settings in order to study the most effective set up regarding participation, refer rates, and costs. In one setting parents visited the well baby clinic, and in two settings babies were screened at home (either in combination with the screening for metabolic diseases or during an intake visit). Screening was performed on 3114 healthy newborns. The setting where universal neonatal hearing screening is integrated with the screening for metabolic diseases, proved to be most efficient and effective. The participation rate of 88.9% was highest in this setting and the overall refer rate (1.4%) was the lowest. The implementation of universal neonatal hearing screening by the well baby clinic nurses was judged to be possible. The results of this study formed the basis for nationwide implementation.

Accuracy of a Screening Tool for Early Identification of Language Impairment.

Purpose: A screening tool called the VTO Language Screening Instrument (VTO-LSI) was developed to enable more uniform and earlier detection of language impairment. This report, consisting of 2 retrospective studies, focuses on the effects of using the VTO-LSI compared to regular detection procedures. Method: Study 1 retrospectively compared VTO-LSI with regular detection procedures. Outcome measure was the detection rate of language impairment among 24-month-old children. Data were retrieved from medical records of children attending a youth health care center. Study 2 retrospectively compared the effects of VTO-LSI and regular detection procedures on the age at referral for diagnostic investigations and the influence of sex. Data were retrieved from medical records from the speech and hearing center and analyzed with multivariate analysis of variance. Results: With the VTO-LSI, significantly more cases with language impairment were identified compared with the regular detection procedure (2.4% vs. 0.4%). In regions where the VTO-LSI was used, girls were almost 2 years younger, and boys were 1 year younger when referred to diagnostic investigations than in regions with regular detection procedures. Conclusion: The VTO-LSI was more effective than regular detection procedures.

Healthcare costs attributable to congenital cytomegalovirus infection.

OBJECTIVE: Congenital cytomegalovirus infection (cCMV) can cause symptoms at birth as well as long-term impairment. This study estimates cCMV-related healthcare costs in the Netherlands in early childhood. DESIGN, SETTING AND PATIENTS: In a nationwide retrospective cohort study, 156 children with cCMV were identified by testing 31 484 neonatal dried blood spots for cCMV. Use of healthcare resources in the first 6 years of life by children with cCMV and a matched cCMV-negative control group were analysed. Mean costs per child were calculated by multiplying healthcare resource use by its reference prices. EXPOSURE: Children with cCMV were compared with cCMV-negative children. MAIN OUTCOME MEASURES: The average total healthcare costs per child were based on the average costs for hospital admissions and consultations by healthcare providers. RESULTS: Mean healthcare costs of children with cCMV (€6113, n=133) were higher than children without cCMV (€3570, n=274), although statistically not significant, with a mean difference of €2544 (95% CI €-451 to €5538). The costs of children with long-term impairment were two times higher in children with cCMV (€17 205) compared with children without cCMV (€8332). CONCLUSIONS: Children with cCMV, especially those with long-term impairment and those symptomatic at birth, accrue higher healthcare costs than cCMV-negative children in the first 6 years of life, although this is not statistically significant. This economic impact is of importance in the evaluation of preventive measures against cCMV. TRIAL REGISTRATION NUMBER: NTR3582.