CHD7 Disorder-Not CHARGE Syndrome-Presenting as Isolated Cochleovestibular Dysfunction.

CHARGE syndrome, characterized by a distinct set of clinical features, has been linked primarily to mutations in the CHD7 gene. Initially defined by specific clinical criteria, including coloboma, heart defects, choanal atresia, delayed growth, and ear anomalies, CHARGE syndrome's diagnostic spectrum has broadened since the identification of CHD7. Variants in this gene exhibit considerable phenotypic variability, leading to the adoption of the term "CHD7 disorder" to encompass a wider range of associated symptoms. Recent research has identified CHD7 variants in individuals with isolated features such as autism spectrum disorder or gonadotropin-releasing hormone deficiency. In this study, we present three cases from two different families exhibiting audiovestibular impairment as the primary manifestation of a CHD7 variant. We discuss the expanding phenotypic variability observed in CHD7-related disorders, highlighting the importance of considering CHD7 in nonsyndromic hearing loss cases, especially when accompanied by inner ear malformations on MRI. Additionally, we underscore the necessity of genetic counseling and comprehensive clinical evaluation for individuals with CHD7 variants to ensure appropriate management of associated health concerns.

Risk Factors for Natural Hearing Evolution in Newborns With Congenital Cytomegalovirus Infection.

Importance: Congenital cytomegalovirus (cCMV) is the major cause of congenital nonhereditary sensorineural hearing loss in children. Currently, criteria to identify infants at increased risk for unfavorable hearing outcome are lacking. Objective: To identify risk factors associated with cCMV-related hearing improvement, hearing deterioration, and late-onset hearing loss. Design, Setting, and Participants: This multicenter cohort study included patients from 6 secondary and tertiary hospitals enrolled in the Flemish CMV registry (Belgium). Newborns with untreated cCMV infection with at least 4-year audiological follow-up were included. Patients who presented with other possible causes of sensorineural hearing loss were excluded. Data were collected for 15 years (January 1, 2007, to February 7, 2022) and analyzed from September 26, 2022, to January 16, 2023. Main Outcomes and Measures: Primary outcome was hearing evolution (per-ear analysis; described as stable hearing, improvement, or deterioration). The association of gestational characteristics, clinical findings, timing of seroconversion, viral load, and hearing status at birth with hearing evolution was investigated using effect sizes (Cramer V, odds ratio [OR], or Hedges g). Results: Of the 387 children, 205 of 385 with nonmissing data were male (53.2%), 113 (29.2%) had a symptomatic infection, and 274 (70.8%) had an asymptomatic infection. Every child was 4 years or older at final hearing evaluation. A total of 701 of 774 ears (90%) showed stable hearing (normal hearing or stable hearing loss since birth) over time. Late-onset hearing loss (normal hearing at birth followed by hearing loss) was present in 43 of 683 ears (6.3%). Among children with hearing loss present at birth, 24 of 34 ears (70.6%) had hearing deterioration, and 6 of 91 ears (6.6%) had hearing improvement. Prematurity was associated with a higher chance of hearing improvement (OR, 12.80; 95% CI, 2.03-80.68). Late-onset hearing loss was more prevalent in a first trimester infection (OR, 10.10; 95% CI, 2.90-34.48). None of the 104 ears of children with a third trimester seroconversion developed late-onset hearing loss. Conclusions and Relevance: Findings of this cohort study support that ongoing audiological follow-up for untreated children with congenital hearing loss is important, as the majority of patients had hearing deterioration. The timing of seroconversion was associated with the risk of developing late-onset hearing loss. These insights can aid in parental counseling, patient stratification, and follow-up. Future research should focus on the effect of treatment, the influence of determined risk factors, and the study of eventual new risk factors in patients at high risk to develop hearing loss.

Vestibular Follow-up Program for Congenital Cytomegalovirus Based on 6 Years of Longitudinal Data Collection.

OBJECTIVES: Congenital cytomegalovirus (cCMV), the leading nongenetic cause of pediatric sensorineural hearing loss, can also affect vestibular function. Literature findings suggest clinical presentation of vestibular loss in cCMV to be as variable as the hearing loss. Still, probably due to the considerable additional burden it entails for both patients and diagnostic centers, longitudinal vestibular follow-up in cCMV is not well-established in clinical practice. Therefore, this study aims to propose an evidence-based vestibular follow-up program with proper balance between its feasibility and sensitivity. DESIGN: In this longitudinal cohort study, 185 cCMV-patients (mean age 3.2 years, SD 1.6 years, range 0.5-6.7 years) were included. Vestibular follow-up data were obtained through lateral video head impulse test (vHIT) and cervical vestibular evoked myogenic potential (cVEMP) evaluations around the ages of 6 months, 1 year, and 2 years. Around 3 and 4.5 years of age, data from vertical vHIT and ocular vestibular evoked myogenic potentials (oVEMP) were also collected. RESULTS: At birth, 55.1% (102/185) of patients were asymptomatic and 44.9% (83/185) were symptomatic. The mean duration of follow-up for all patients was 20.8 (SD 16.3) months (mean number of follow-up assessments: 3.2, SD 1.5). Vestibular loss occurred at some point during follow-up in 16.8% (31/185) of all patients. Six percent (10/164) of patients with normal vestibular function at first assessment developed delayed-onset vestibular loss; 80.0% (8/10) of these within the first 2 years of life. Vestibular deterioration was reported both in patients who had been treated with postnatal antiviral therapy and untreated patients. At final evaluation, both the semicircular and the otolith system were impaired in the majority of vestibular-impaired ears (29/36, 80.6%). Dysfunctions limited to the semicircular system or the otolith system were reported in 4 (4/36, 11.1%) and 3 (3/36, 8.3%) ears, respectively. The occurrence of vestibular loss was highest in patients with first trimester seroconversion (16/59, 27.1%) or with an unknown timing of seroconversion (13/71, 18.3%), patients with sensorineural hearing loss (16/31, 51.6%), and patients with periventricular cysts on magnetic resonance imaging (MRI) (7/11, 63.6%). CONCLUSIONS: Longitudinal vestibular follow-up, most intensively during the first 2 years of life, is recommended in cCMV-patients with vestibular risk factors (first trimester or unknown timing of seroconversion; sensorineural hearing loss; periventricular cysts on MRI). If those risk factors can be ruled out, a single evaluation early in life (around 6 months of age) might be sufficient. Both semicircular and otolith system evaluation should be part of the follow-up program, as partial losses were reported.

Vestibular Infant Screening-Flanders: What is the Most Appropriate Vestibular Screening Tool in Hearing-Impaired Children?

OBJECTIVES: As children with sensorineural hearing loss have an increased risk for vestibular impairment, the Vestibular Infant Screening-Flanders project implemented a vestibular screening by means of cervical vestibular evoked myogenic potentials (cVEMP) at the age of 6 months for each child with hearing loss in Flanders (Belgium). Given that vestibular deficits can affect the child's development, this vestibular screening should allow early detection and intervention. However, less is currently known about which screening tool would be the most ideal and how vestibular impairment can evolve. Therefore, this study aimed to determine the most appropriate tool to screen for vestibular deficits, to assess the necessity of vestibular follow-up, and to set clinical guidelines for vestibular screening in children with hearing loss. DESIGN: In total, 71 children with congenital or early-onset sensorineural hearing loss were enrolled (mean age at first appointment = 6.7 months). Follow-up was provided at 6 months, 1, 2, and 3 years of age. Below three years of age, the video Head Impulse Test (vHIT) of the horizontal semicircular canals (SCC), the cVEMP, and the rotatory test at 0.16, 0.04, and 0.01 Hz were applied. At 3 years of age, the vHIT of the vertical SCC and ocular vestibular evoked myogenic potentials (oVEMP) were added. To evaluate early motor development, the Alberta Infant Motor Scale (AIMS) results at 6 months and 1-year old were included. RESULTS: At 6 months of age, the highest success rate was obtained with the cVEMP (90.0%) compared to the vHIT (70.0%) and the rotatory test (34.3-72.9%). Overall, vestibular deficits were found in 20.0% of the children, consisting of 13.9% with both SCC and otolith deficits (bilateral: 9.3%, unilateral: 4.6%), and 6.1% with unilateral isolated SCC (4.6%) or otolith (1.5%) deficits. Thus, vestibular deficits would not have been detected in 4.6% of the children by only using the cVEMP, whereas 1.5% would have been missed when only using the vHIT. Although vestibular deficits were more frequently found in severe to profound hearing loss (28.6%), characteristics of vestibular function were highly dependent on the underlying etiology. The AIMS results showed significantly weaker early motor development in children with bilateral vestibular deficits ( p = 0.001), but could not differentiate children with bilateral normal vestibular function from those with unilateral vestibular deficits ( p > 0.05). Progressive or delayed-onset vestibular dysfunction was only found in a few cases (age range: 12-36 months), in which the hearing loss was mainly caused by congenital cytomegalovirus (cCMV). CONCLUSIONS: The cVEMP is the most feasible screening tool to assess vestibular function in 6-months-old children with hearing loss. Although the majority of children with vestibular deficits are detected with the cVEMP, the vHIT seems even more sensitive as isolated SCC deficits are associated with specific etiologies of hearing loss. As a result, the cVEMP is an appropriate vestibular screening tool, which is advised at least in severe to profound hearing loss, but certain etiologies require the addition of the vHIT (i.e., cCMV, meningitis, cochleovestibular anomalies with or without syndromic hearing loss).

Risk Factors for Hearing Loss at Birth in Newborns With Congenital Cytomegalovirus Infection.

Importance: With a prevalence between 0.2% and 6.1% of all live births, congenital cytomegalovirus (cCMV) infection is a major cause of congenital nonhereditary sensorineural hearing loss. Despite the large amount of research on cCMV-related hearing loss, it is still unclear which newborns are at risk of hearing loss. Objective: To identify independent risk factors for cCMV-related congenital hearing loss and predictors of hearing loss severity at birth. Design, Setting, and Participants: This cross-sectional study of newborns with cCMV infection used data included in the Flemish CMV registry that was collected from 6 secondary and tertiary hospitals in Flanders, Belgium, over 15 years (January 1, 2007, to February 7, 2022). Data were analyzed March 3 to October 19, 2022. Patients were included in the study after confirmed diagnosis of cCMV infection and known hearing status at birth. Patients who presented with other possible causes of sensorineural hearing loss were excluded. Main Outcomes and Measures: Primary outcome was hearing status at birth. Clinical, neurological, and laboratory findings along with the timing of seroconversion and blood viral load were separately considered as risk factors. Binary logistic regression was performed to identify independent risk factors for congenital hearing loss in newborns with cCMV. Effect sizes were measured using Hedges g, odds ratio, or Cramer V. Results: Of the 1033 newborns included in the study (553 of 1024 [54.0%] boys), 416 (40.3%) were diagnosed with symptomatic cCMV infection and 617 (59.7%) with asymptomatic cCMV infection. A total of 15.4% of the patients (n = 159) presented with congenital hearing loss; half of them (n = 80 [50.3%]) had isolated hearing loss. The regression model revealed 3 independent risk factors for congenital hearing loss: petechiae at birth (adjusted odds ratio [aOR], 6.7; 95% CI, 1.9-23.9), periventricular cysts on magnetic resonance imaging (MRI; aOR, 4.6; 95% CI, 1.5-14.1), and seroconversion in the first trimester (aOR, 3.1; 95% CI, 1.1-9.3). Lower viral loads were seen in patients with normal hearing compared with those with congenital hearing loss (median [IQR] viral load, 447.0 [39.3-2345.8] copies per milliliter of sample [copies/mL] vs 1349.5 [234.3-14 393.0] copies/mL; median difference, -397.0 [95% CI, -5058.0 to 174.0] copies/mL). Conclusions and Relevance: Findings of this cross-sectional study suggest that newborns with cCMV infection and petechiae at birth, periventricular cysts on MRI, or a seroconversion in the first trimester had a higher risk of congenital hearing loss. Clinicians may use these risk factors to counsel parents in the prenatal and postnatal periods about the risk of congenital hearing loss. Moreover, linking clinical features to hearing loss may provide new insights into the pathogenesis of cCMV-related hearing loss. The importance of viral load as a risk factor for congenital hearing loss remains unclear.

Predicting Early Vestibular and Motor Function in Congenital Cytomegalovirus Infection.

OBJECTIVES: Congenital cytomegalovirus (cCMV) can affect vestibular function, which is an important cornerstone for early motor development. This study aims to identify risk factors for early vestibular dysfunction with severe repercussions on the motor outcome. METHODS: This prospective cohort study included 169 cCMV-patients with complete vestibular assessment (lateral video Head Impulse Test and cervical Vestibular Evoked Myogenic Potentials) before the age of 18 months (mean 8.9, standard deviation 3.27 months). Motor results using the Alberta Infant Motor Scale were collected in 152 of these patients. Logistic and linear regression models were applied to identify risk factors for the vestibular and motor outcomes, respectively. RESULTS: The odds of developing early vestibular dysfunction were 6 times higher in patients presenting with hearing loss at birth compared to those born with normal hearing (p = .002). Within the latter group, significant predictors for vestibular dysfunction were (delayed-onset) hearing impairment at the time of vestibular testing (p = .003) and the presence of periventricular cysts on magnetic resonance imaging (p = .005). Remarkably, none of the patients infected during the third trimester of pregnancy (n = 14) developed early vestibular dysfunction. On average, vestibular-impaired patients had a z-score on the Alberta Infant Motor Scale that was 1.17 points lower than patients without vestibular deficit (p < .001). CONCLUSION: Early vestibular loss can have a significant adverse effect on motor development. Hearing and cranial imaging findings could facilitate the widespread implementation of a (targeted) vestibular assessment approach in the cCMV-population. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1757-1765, 2023.

Long-term anatomic and functional outcome of pediatric myringoplasty in primary and revision cases.

OBJECTIVES: To evaluate the long-term anatomical and functional results of myringoplasty in a large cohort of children and analyse factors determining outcome of surgery. METHODS: A retrospective analysis of 469 cases of primary and revision pediatric myringoplasties conducted between 2003 and 2018 at the Ghent University Hospital was performed. Anatomical success was defined as an intact tympanic membrane postoperatively. Overall success was defined as an intact tympanic membrane, preservation or improvement of hearing and an ear free from otitis media with effusion, atelectasis, ear discharge and myringitis. The impact of different variables on outcome was investigated by univariate analysis. RESULTS: In primary cases, anatomical success was achieved in 96.8% and 94.3% at early respectively late evaluation (after 1 resp. 12 months). Overall success was achieved in 65.4% and 68.5% at early and late evaluation respectively. In revision cases, early anatomical and overall success were achieved in 96.8% and 53.8%, dropping to respectively 88.9% and 47.1% at late evaluation. In primary cases, presence of bilateral perforations was a significant predictor of a negative anatomical outcome. Further analysis of anatomical, audiological, and overall success rates in primary and revision cases could not withhold any significant predictors. CONCLUSION: Anatomical success rates of myringoplasty in children are high, in primary as well as revision surgery. When taking the functional status in account however, success rates are lower. The presence of a bilateral perforation predicts a worse outcome with higher anatomical failure rates. No other factors with significant predictive effect on outcome were identified.

Hearing Loss in Stickler Syndrome: An Update.

Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory manifestations. Its main symptoms are high myopia, retinal detachment, joint hypermobility, early osteoarthritis, cleft palate, midfacial hypoplasia, micrognathia and hearing loss. Large phenotypical variability is apparent and partly explained by the underlying genetic heterogeneity, including collagen genes (COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3) and non-collagen genes (BMP4, LRP2, LOXL3). The most frequent type of Stickler syndrome (COL2A1) is characterized by a rather mild high-frequency sensorineural hearing loss in about half of the patients. COL11A1- and COL11A2-related Stickler syndrome results in more frequent hearing loss, being moderate and involving all frequencies. Hearing loss in the rarer types of Stickler syndrome depends on the gene expression in the cochlea, with moderate to severe downsloping hearing loss for Stickler syndrome caused by biallelic type IX collagen gene mutations and none or mild hearing loss for the non-collagen genes. Inherent to the orofacial manifestations, middle ear problems and temporary conductive hearing loss, especially at young age, are also prevalent. Consequently, hearing loss should be actively sought for and adequately treated in Stickler syndrome patients given its high prevalence and the concomitant visual impairment in most patients.

Three Years of Vestibular Infant Screening in Infants With Sensorineural Hearing Loss.

OBJECTIVES: Although vestibular deficits are more prevalent in hearing-impaired children and can affect their development on many levels, a pediatric vestibular assessment is still uncommon in clinical practice. Since early detection may allow for timely intervention, this pioneer project has implemented a basic vestibular screening test for each six-month-old hearing-impaired infant in Flanders, Belgium. This study aims to report the vestibular screening results over a period of three years and to define the most important risk factors for abnormal vestibular screening results. METHODS: Cervical Vestibular Evoked Myogenic Potentials with bone-conduction were used as a vestibular screening tool in all reference centers affiliated to the Universal Newborn Hearing Screening Program in Flanders. From June 2018 until June 2021, 254 infants (mean age: 7.4 months, standard deviation: 2.4 months) with sensorineural hearing loss were included. RESULTS: Overall, abnormal vestibular screening results were found in 13.8% (35 of 254) of the infants. The most important group at risk for abnormal vestibular screening results were infants with unilateral or bilateral severe to profound sensorineural hearing loss (20.8%, 32 of 154) (P < .001, odds ratio = 9.16). Moreover, abnormal vestibular screening results were more prevalent in infants with hearing loss caused by meningitis (66.7%, 2 of 3), syndromes (28.6%, 8 of 28), congenital cytomegalovirus infection (20.0%, 8 of 40), and cochleovestibular anomalies (19.2%, 5 of 26). CONCLUSIONS: The vestibular screening results in infants with sensorineural hearing loss indicate the highest risk for vestibular deficits in severe to profound hearing loss, and certain underlying etiologies of hearing loss, such as meningitis, syndromes, congenital cytomegalovirus, and cochleovestibular anomalies.

Negative Molecular Diagnostics in Non-Syndromic Hearing Loss: What Next?

Congenital hearing loss has an impact on almost every facet of life. In more than 50% of cases, a genetic cause can be identified. Currently, extensive genetic testing is available, although the etiology of some patients with obvious familial hearing loss remains unknown. We selected a cohort of mutation-negative patients to optimize the diagnostic yield for genetic hearing impairment. In this retrospective study, 21 patients (17 families) with negative molecular diagnostics for non-syndromic hearing loss (gene panel analysis) were included based on a positive family history with a similar type of hearing loss. Additional genetic testing was performed using a whole exome sequencing panel (WESHL panel v2.0) in four families with the strongest likelihood of genetic hearing impairment. In this cohort (n = 21), the severity of hearing loss was most commonly moderate (52%). Additional genetic testing revealed pathogenic copy number variants in the STRC gene in two families. In summary, regular re-evaluation of hearing loss patients with presumably genetic etiology after negative molecular diagnostics is recommended, as we might miss newly discovered deafness genes. The switch from gene panel analysis to whole exome sequencing or whole genome sequencing for the testing of congenital hearing loss seems promising.

Cranial ultrasound and MRI: complementary or not in the diagnostic assessment of children with congenital CMV infection?

Whether or not cranial ultrasound (crUS) and cerebral magnetic resonance imaging (MRI) have both a place in the assessment of children with congenital cytomegalovirus infection (cCMV) remains a topic of discussion between research groups. Literature suggests that MRI is indicated only in children with abnormal crUS.In Flanders, Belgium, combined crUS and MRI was performed on 639 children with cCMV, referred for diagnostic assessment. Cranial US was classified as abnormal in the presence of striatal vasculopathy, calcifications, cysts, cystic germinolysis, and/or ventriculomegaly. MRI findings were classified as abnormal in the presence of gyration disorders, cerebellar abnormalities, ventriculomegaly, cysts, or pathologic white matter lesions.One in five children (93/480) with normal crUS showed abnormal findings on MRI. Of them, 85 (91.4%) were classified as symptomatic. In 37 of those 93 children (39.8%), classification as severely symptomatic was made based on MRI lesions alone. MRI and crUS proved to be complementary in the assessment of CNS involvement in children with cCMV. Long-term studies are needed to evaluate the importance of this finding with respect to outcome and benefit of therapy in this particular subgroup of patients with cCMV infection.Conclusion: Our findings support an enhanced role of MRI in the diagnosis of CNS involvement in children with cCMV infection. The ideal assessment should include both imaging techniques, as the strengths of each test compensate for the other's weaknesses. What is Known: • Congenital CMV infection involves the central nervous system with direct injury to and possible disruption of brain development. • Experts suggest that MRI is indicated only in children with abnormal crUS. What is New: • In almost 20% of our children with a normal cranial ultrasound, abnormalities were detected on MRI. • Our results suggest that performing both MRI and cranial US is important to obtain a complete assessment of central nervous system involvement in children with cCMV.

Twelve years of neonatal hearing screening: audiological and etiological results.

PURPOSE: Most developed countries have implemented some form of universal newborn hearing screening program. Early identification and rehabilitation of congenital hearing loss is important in functional outcome, and the need to identify the cause of hearing impairment has become clear. We aimed to evaluate audiological and etiological outcomes in a large group of patients with failed neonatal hearing screening. METHODS: We performed a retrospective chart analysis of patients who were referred to our tertiary referral center after failing neonatal hearing screening during a 12-year period (2007-2019). Screening was based on automated auditory brainstem response (AABR) or a combined approach of AABR and auditory steady-state response (ASSR) with chirp stimulus. Extensive audiometric testing was performed to confirm and determine the type and degree of hearing loss. In case of permanent hearing loss, a standardized etiological protocol was followed to determine the cause. RESULTS: Of the 802 referred newborns, hearing loss was confirmed by diagnostic ABR in 78%. Main causes of hearing loss included otitis media with effusion (56%, higher in patients screened by AABR/ASSR compared to AABR), a genetic disorder (12%), congenital cytomegalovirus infection (cCMV, 5%) and atresia/stenosis of the external ear canal (5%). Of the patients with permanent hearing loss, 15% showed changes in hearing loss severity over time. CONCLUSION: In the majority of newborns referred after failing universal neonatal hearing screening, hearing loss could be confirmed. The leading cause was reversible hearing loss due to otitis media with effusion, but hearing loss proved permanent in about 35% of referred newborns, with genetics as predominant cause. Follow-up of congenital hearing loss patients is important as deterioration as well as improvement was observed over time.

Congenital Unilateral Hearing Loss: Characteristics and Etiological Analysis in 121 Patients.

OBJECTIVE: To describe the characteristics and etiological analysis in patients with congenital unilateral hearing loss. STUDY DESIGN: Retrospective cohort analysis. SETTING: Tertiary referral center. PATIENTS: Children with permanent congenital unilateral hearing loss born between 2007 and 2018. Patients were referred after universal newborn hearing screening or by a colleague to confirm the diagnosis and perform etiological examinations. MAIN OUTCOME MEASURES: Hearing loss type, severity, and evolution linked with the results of etiological testing. RESULTS: In the 121 included children, aural atresia is the leading cause of congenital unilateral hearing loss (32%), followed by structural anomalies (19%) and cCMV (13%), whereas 24% remained idiopathic after etiological work-up. Severity is mainly moderately severe (33% with 56-70 dB hearing loss, majority aural atresia) or profound (31% with > 90 dB hearing loss, predominantly cochlear nerve deficiency). Syndromic features were present in 26%. Although discussed with all parents, only 26% of the children regularly used hearing amplification. CONCLUSIONS: Congenital conductive unilateral hearing loss is mainly caused by aural atresia, which proportion in congenital unilateral hearing loss proved higher than previously reported. Cochlear nerve deficiency and cCMV are the predominant etiologies of congenital unilateral sensorineural hearing loss. Etiological work-up in affected patients is mandatory as it might impact the approach, and syndromic features should be actively searched for.

Multidisciplinary Approach to the Child with Sex Chromosomal Mosaicism Including a Y-Containing Cell Line.

Children born with sex chromosomal mosaicism including material derived from the Y chromosome may present with a broad phenotypical spectrum. Both boys and girls can present with Turner features and functional health problems typically associated with Turner syndrome, but the presence of Y-chromosomal material can modify some aspects of the condition. We retrospectively analyzed the results of our cohort of 21 individuals (14 boys, 7 girls) with sex chromosomal mosaicism including Y-derived material followed at Ghent University Hospital according to our local multidisciplinary Turner surveillance protocol. Results were compared with literature data, focusing on similarities and differences between girls and boys with this condition. Age at diagnosis was lower in boys compared to girls but the difference was not significant. Short stature is a key feature of the condition both in girls and boys, but skeletal maturation may be different between groups. The effects of growth-hormone therapy remain unclear. Cardiac (33%), ear-nose- throat (ENT) (77.8%) and renal (28.6%) problems were as prevalent in boys as in girls from our cohort, and did not differ from literature data. In line with literature reports, a significant difference in the presence of premalignant germ cell tumors between males (0%) and females (42.9%) was found (p = 0.026). Taken together, this study demonstrates the similarities between girls with Turner syndrome and children with sex chromosomal mosaicism including Y-derived material, regardless of the child's gender. Nowadays, girls with Turner syndrome are offered a dedicated multidisciplinary follow-up in many centers. We advocate a similar follow-up program for all children who have sex chromosomal mosaicism that includes Y-derived material, with special attention to growth, cardiac and ear-nose-throat problems, gonadal function and malignancies.

Congenital cytomegalovirus infection registry in flanders: opportunities and pitfalls.

In 2007, a prospective multicentre registry was set up to collect data on incidence and outcome of children with congenital cytomegalovirus infection in Flanders. A consensus was reached about management and follow up of cytomegalovirus-infected children. With this registration, we aimed at gathering information on congenital cytomegalovirus infection in Flanders and evaluating the consensus on management and therapy. Children with proven congenital cytomegalovirus infection were eligible for registration in the database. Information on prenatal and neonatal management, therapy and follow up until 6 years was obtained. Between 2007 and 2017, 686 children were registered. Data on the prenatal and neonatal characteristics in children with congenital cytomegalovirus infection are reported.Conclusion: In this article, we report on our experience of conducting a registry for cCMV in Flanders. Eleven years of collecting data on CMV in a multicenter setting have shown us some pitfalls and opportunities. We address some of the problems and aim at improving our data gathering. We encourage other groups to share their data. Better knowledge of the burden of the disease will be important to guide future management strategies.

Congenital CMV-Associated Hearing Loss: Can Brain Imaging Predict Hearing Outcome?

OBJECTIVES: Congenital cytomegalovirus (cCMV) infection is the leading cause of nonhereditary sensorineural hearing loss in childhood and is also associated with CNS abnormalities. The main objective is to investigate the prognostic value of neonatal cranial ultrasound (cUS) and cranial magnetic resonance imaging (cMRI) in predicting long-term hearing outcome in a large cohort of cCMV-infected symptomatic and asymptomatic patients. DESIGN: Data were prospectively collected from a multicentre Flemish registry of children with cCMV infection born between 2007 and 2016. Neonatal cUS and cMRI scans were examined for lesions related to cCMV infection. Audiometric results at different time points were analyzed. The imaging and audiometric results were linked and diagnostic values of cUS and cMRI were calculated for the different hearing outcomes. RESULTS: We were able to include 411 cCMV patients, of whom 40% was considered symptomatic at birth. Cranial ultrasound abnormalities associated with cCMV infection were found in 76 children (22.2% of the cUS scans), whereas cMRI revealed abnormalities in 74 patients (26.9% of the cMRI scans). A significant relation could be found between the presence of cUS or cMRI abnormalities and hearing loss at baseline and last follow-up. Cranial ultrasound and cMRI findings were not significantly correlated with the development of delayed-onset hearing loss. Specificity and sensitivity of an abnormal cUS to predict hearing loss at final follow-up were 84% and 43%, respectively compared with 78% and 39% for cMRI. Normal cUS and cMRI findings have a negative predictive value of 91% and 92%, respectively, for the development of delayed-onset hearing loss. CONCLUSIONS: Neuroimaging evidence of CNS involvement in the neonatal period is associated with the presence of hearing loss in children with a cCMV infection. Imaging abnormalities are not predictive for the development of delayed-onset hearing loss.

Vestibular Function in Children With a Congenital Cytomegalovirus Infection: 3 Years of Follow-Up.

OBJECTIVES: Congenital cytomegalovirus (cCMV) infection is the most common nongenetic cause of sensorineural hearing loss in children. Due to the close anatomical relationship between the auditory and the vestibular sensory organs, cCMV can also be an important cause of vestibular loss. However, the prevalence and nature of cCMV-induced vestibular impairment is still underexplored. The aim of this study was to investigate the occurrence and characteristics of vestibular loss in a large group of cCMV-infected children, representative of the overall cCMV-population. DESIGN: Ninety-three children (41 boys, 52 girls) with a confirmed diagnosis of cCMV were enrolled in this prospective longitudinal study. They were born at the Ghent University Hospital or referred from another hospital for multidisciplinary follow-up in the context of cCMV. The test protocol consisted of regular vestibular follow-up around the ages of 6 months, 1 year, 2 years, and 3 years with the video Head Impulse Test, the rotatory test, and the cervical Vestibular Evoked Myogenic Potential test. RESULTS: On average, the 93 patients (52 asymptomatic, 41 symptomatic) were followed for 10.2 months (SD: 10.1 mo) and had 2.2 examinations (SD: 1.1). Seventeen (18%) patients had sensorineural hearing loss (7 unilateral, 10 bilateral). Vestibular loss was detected in 13 (14%) patients (7 unilateral, 6 bilateral). There was a significant association between the occurrence of hearing loss and the presence of vestibular loss (p < 0.001), with 59% (10/17) vestibular losses in the group of hearing-impaired children compared to 4% (3/76) in the group of normal-hearing subjects. In the majority of the cases with a vestibular dysfunction (85%, 11/13), both the semicircular canal system and the otolith system were affected. The remaining subjects (15%, 2/13) had an isolated semicircular canal dysfunction. Sixty-one patients already had at least one follow-up examination. Deterioration of the vestibular function was detected in 6 of them (10%, 6/61). CONCLUSIONS: cCMV can impair not only the auditory but also the vestibular function. Similar to the hearing loss, vestibular loss in cCMV can be highly variable. It can be unilateral or bilateral, limited or extensive, stable or progressive, and early or delayed in onset. As the vestibular function can deteriorate over time and even normal-hearing subjects can be affected, vestibular evaluation should be part of the standard otolaryngology follow-up in all children with cCMV.

The impact of cleft lip and/or palate on parental quality of life: A pilot study.

BACKGROUND: Cleft lip and/or palate (CL/CP/CLP) is one of the most common congenital anomalies. Children may suffer from a variety of health problems including difficulties with feeding and speech, middle ear problems, hearing loss and associated psychosocial concerns. The extent of impact of this disorder on the parents, however, has not yet been thoroughly evaluated. This pilot study was performed to evaluate the impact of having a child with CL/CP/CLP on the parents' quality of life (QoL) and family functioning and to compare between cleft subgroups. METHODS: Forty-five parents with children aged 6 months to 6 years with CL/CP/CLP, followed by the multidisciplinary orofacial cleft team of Ghent University Hospital, completed following standardized questionnaires: Impact on Family Scale (IOFS), Family Impact Scale (FIS) and Care-Related Quality of Life Instrument (CarerQoL). Subgroups were compared with diverse unpaired statistical tests. RESULTS: Younger children (6m-2y) with CL/CP/CLP entail more impact on parental QoL compared to children aged 2-4y old (p=0.04, ε²=0.15/p=0.02, ε²=0.17/p=0.02, ε²=0.17). Families from children with a syndromic cleft also encounter more impact (p=0.04, r=0.32 /p=0.01, r=0.37 /p=0.008, r=0.40/p=0.003, r=0.45). Prenatal orofacial cleft diagnosis is associated with a higher reporting of family conflicts (p=0.04, r=0.32). In case of non-syndromic clefts, families having children with CLP report more family conflicts compared to CL or CP (p=0.02, ε²=0.46). Parental education and number of children within the household showed no significant impact on parental QoL. CONCLUSION: This cross-sectional study confirms that having a child with CL/CP/CLP impacts the parental QoL. This study was performed as a pilot-study for larger multicentre studies, future development of effective screening tools and identification of subgroups at risk. Long-term multidisciplinary follow-up should involve family-centred support.

Ear- and hearing-related impact on quality of life in children with cleft palate: Development and pretest of a health-related quality of life (HRQOL) instrument.

OBJECTIVES: To investigate to what extent middle ear problems and associated hearing loss affect quality of life (QoL) of children born with a cleft palate. METHODS: Fifty-five children aged between 6 and 18 years, born with non-syndromic cleft palate ±â€¯cleft lip (CP/L) were included. A new health-related quality of life (HRQOL) questionnaire was generated with consideration of the following domains of QoL: communication, hearing loss, physical symptoms, limitation of activities and socio-emotional impact. RESULTS: Major psychosocial problems were not reported in the majority of children as a result of their ear and hearing problems. However, according to their parents, 2 out of 3 children, had difficulty speaking clearly and understandably. These communication problems led to behavioural problems and social isolation in 1 out of 5 children. Scholastic achievement was negatively influenced by two factors: hearing loss and sleep disturbance due to ear problems. CONCLUSIONS: To our knowledge this is the first study to quantitatively measure the ear- and hearing-related impact on QoL in children born with CP/L. Large-scale, multicentre studies are needed to further research and expand on the findings of this pilot study.

Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis.

PURPOSE: To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. METHODS: We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. RESULTS: Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006-0.0060). CONCLUSION: MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.