phox2ba: The Potential Genetic Link behind the Overlap in the Symptomatology between CHARGE and Central Congenital Hypoventilation Syndromes.

CHARGE syndrome typically results from mutations in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). CHD7 is involved in regulating neural crest development, which gives rise to tissues of the skull/face and the autonomic nervous system (ANS). Individuals with CHARGE syndrome are frequently born with anomalies requiring multiple surgeries and often experience adverse events post-anesthesia, including oxygen desaturations, decreased respiratory rates, and heart rate abnormalities. Central congenital hypoventilation syndrome (CCHS) affects ANS components that regulate breathing. Its hallmark feature is hypoventilation during sleep, clinically resembling observations in anesthetized CHARGE patients. Loss of PHOX2B (paired-like homeobox 2b) underlies CCHS. Employing a chd7-null zebrafish model, we investigated physiologic responses to anesthesia and compared these to loss of phox2b. Heart rates were lower in chd7 mutants compared to the wild-type. Exposure to tricaine, a zebrafish anesthetic/muscle relaxant, revealed that chd7 mutants took longer to become anesthetized, with higher respiratory rates during recovery. chd7 mutant larvae demonstrated unique phox2ba expression patterns. The knockdown of phox2ba reduced larval heart rates similar to chd7 mutants. chd7 mutant fish are a valuable preclinical model to investigate anesthesia in CHARGE syndrome and reveal a novel functional link between CHARGE syndrome and CCHS.

A case of migraine treatment in a patient with a clinical diagnosis of CHARGE syndrome using onabotulinum toxin A.

CHARGE syndrome is a genetic disorder that affects multiple organ and sensory systems. Cranial nerve involvement is one of the key clinical diagnostic criteria. We present the case of an 8-year-old girl with CHARGE syndrome, associated right-sided facial palsy, and chronic severe migraines, that were intractable to medical treatment. At age 6, onabotulinum toxin A was used to weaken the contralateral non-paralyzed side of her face to address her stigmatizing asymmetry. Onabotulinum toxin A chemodenervation was performed on the left lower lip depressors to relax the muscles and improve left lower lip position. Coincidentally, it was noted that with these treatments, migraine symptoms resolved. As the chemodenervation subsided over the next 3-4 months, the severe migraines returned. Continued treatment with onabotulinum toxin A injections every 3 months has resulted in ongoing improvements in facial symmetry and migraine control. Onabotulinum toxin A is a well-known treatment of chronic migraine. Injections are usually directed to the occipitalis, frontalis, and corrugator muscles. The literature has no reports of injections to the lower lip depressors as a useful therapy for migraine, making the results from this case unique.

New Feeding Assessment Scale for individuals with genetic syndromes: Validity and reliability in the CHARGE syndrome population.

AIM: To develop a feeding scale for parents/care givers of individuals of all ages with genetic syndromes experiencing extensive feeding and swallowing problems. Second, to assess its validity and reliability in CHARGE syndrome. METHODS: The new Feeding Assessment Scale (FAS) was adapted from a scale for children who need prolonged tube feeding (Paediatric Assessment Scale for Severe Feeding Problems, PASSFP). Ten parents piloted the new scale before it was sent out with the PASSFP and feeding history questions. A subset completed the new scale again 4-8 weeks later. RESULTS: One hundred parents of individuals with CHARGE syndrome participated from around the world. The new scale had good construct validity, with a significant effect for an increased number of feeding risk factors having higher scale scores (P < 0.001). Face validity was high, as scores significantly differed between individuals whose parents identified their feeding difficulties as very mild, mild, moderate, severe and very severe (P < 0.001). Test-retest reliability (r = 0.94, P < 0.001) and internal consistency (Cronbach's alpha 0.91) were both high. There was significant convergent validity between the new scale and the PASSFP (r = -0.79, P < 0.001). CONCLUSIONS: This new tool is reliable and valid for parents/care givers of individuals with CHARGE syndrome. It can be used to assess the current severity of feeding difficulties and to track progress before and after treatment. It expands upon previous existing tools in that it can be used in both individuals who are not tube fed, as well as in those who are, as well as across the life-span.

Canadian medical schools' preclerkship paediatric clinical skills curricula: How can we improve?

BACKGROUND: Little is known about how Canadian medical schools teach paediatric clinical skills (history and physical exam) to preclerkship students, or its cost to the institutions. METHODS: Clinical skills program directors from all 17 Canadian medical schools were contacted to complete a questionnaire focused on teaching methods, and barriers/strengths of their Preclerkship Paediatric Clinical Skills program. RESULTS: Seventeen schools (100% response rate) participated. Seven schools (41%) do not introduce paediatric clinical skills until the second year of medicine. Half of the schools (53%) dedicate <10 total hours to preclerkship paediatric clinical skills. Fifty-nine per cent have ≤6 total hours of hands-on paediatric patient interaction (real or simulated). Medical students were least likely to be exposed to the infant age group (age 1 to 24 months). Twelve schools (71%) used simulated parent/child dyads. The most significant barriers identified by programs were limited time for sessions and patient availability. We describe one sample medical school's simulated parent/paediatric patient program where every student has hands-on learning with paediatric patients of all ages (program cost $938/student). DISCUSSION: This study is the first to summarize Canadian preclerkship paediatric clinical skills programs, among which there is great variability and commonly experienced barriers. Many students are not being exposed to all age groups of paediatric patients before their clerkship years. Medical schools can use this information to strengthen this important and challenging aspect of the curriculum, while being mindful of its fiscal implications.

A case report and literature review: Factitious disorder imposed on another and malingering by proxy.

Factitious disorder imposed on another (FDIA) and malingering by proxy (MAL-BP) are two forms of underreported child maltreatment that should remain on physicians' differential. This case of a 2-year-old boy, which spans 6 years, reveals the complexity in and difficulties with diagnosis. Key features include the patient's mother using advanced medical jargon to report multiple disconnected concerns and visits to numerous providers. As a result, the patient underwent many investigations which often revealed normal findings. FDIA was suspected by the paediatrician, especially following corroboration with the child's day care and past primary health care provider. This case demonstrates the possible overlap in diagnoses, which are characterized by a lack of consistent presentation and deceitful caregivers, often complicated by true underlying illness. The authors use clinical experience and limited existing literature to empower paediatricians to confidently diagnose and report FDIA and MAL-BP to limit future harm to children.

Etiology and functional validation of gastrointestinal motility dysfunction in a zebrafish model of CHARGE syndrome.

CHARGE syndrome is linked to autosomal-dominant mutations in the CHD7 gene and results in a number of physiological and structural abnormalities, including heart defects, hearing and vision loss, and gastrointestinal (GI) problems. Of these challenges, GI problems have a profound impact throughout an individual's life, resulting in increased morbidity and mortality. A homolog of CHD7 has been identified in the zebrafish, the loss of which recapitulates many of the features of the human disease. Using a morpholino chd7 knockdown model complemented by a chd7 null mutant zebrafish line, we examined GI structure, innervation, and motility in larval zebrafish. Loss of chd7 resulted in physically smaller GI tracts with normal epithelial and muscular histology, but decreased and disorganized vagal projections, particularly in the foregut. chd7 morphant larvae had significantly less ability to empty their GI tract of gavaged fluorescent beads, and this condition was only minimally improved by the prokinetic agents, domperidone and erythromycin, in keeping with mixed responses to these agents in patients with CHARGE syndrome. The conserved genetics and transparency of the zebrafish have provided new insights into the consequences of chd7 gene dysfunction on the GI system and cranial nerve patterning. These findings highlight the opportunity of the zebrafish to serve as a preclinical model for studying compounds that may improve GI motility in individuals with CHARGE syndrome.

Adolescent interviewing skills: effect of feedback.

BACKGROUND: Communicating with adolescent patients can be challenging. Our study assessed the effect of structured feedback following a standardised patient (SP) encounter on postgraduate year-1 (PGY1) residents' adolescent-specific communication skills. Communicating with adolescent patients can be challenging METHODS: A two-group, prospective, double-blind randomised control study design was employed. Measures were taken before and after the intervention. PGY1 residents conducted a 30-minute interview with an SP adolescent-mother pair, who then individually scored the resident's performance using the validated Structured Communication Adolescent Guide (SCAG). PGY1s were randomised to receive either structured feedback following the interview (feedback group) or no feedback (no feedback group). All residents completed a second interview 4-6 weeks later. Scores were analysed using unpaired t-tests. RESULTS: Thirty-eight residents completed both interviews. The mean total-item and mean global scores for the first interview did not differ significantly between the feedback (n = 21) and no-feedback group (n = 17). The mean total-item scores for the feedback group [first interview: 34.19 ± 10.19 (adolescent); 36.33 ± 9.77 (mother)] improved significantly for the second interview [45.17 ± 6.22 (adolescent); 44.71 ± 6.72 (mother); p = 0.002 and 0.003, respectively]. The mean global scores also improved significantly from the first interview [27.00 ± 6.49 (adolescent); 27.47 ± 6.50 (mother)] to the second interview [34.05 ± 3.30 (adolescent); 31.19 ± 3.85 (mother); p = 0.001 and 0.03, respectively]. No significant improvement in the mean total-item or mean global rating was observed in the no feedback group. CONCLUSIONS: Structured feedback following a single adolescent and mother SP encounter resulted in significant improvement in the adolescent-specific communication skills of PGY1s in performing an adolescent interview.

Adolescent narrative comments in assessing medical students.

BACKGROUND: Adolescent medical interviewing is a difficult topic to teach and assess. Programmatic assessment has been gaining interest in medical teaching, and shifts the mode of assessment from the traditional assessment of learning (e.g. written exams) to the assessment for learning (e.g. feedback). The Structured Communication Adolescent Guide (SCAG) is a programmatic assessment tool that allows an adolescent patient to provide three types of feedback (written, numeric, grade) to a medical student in an authentic clinical workplace. METHODS: We conducted a qualitative analysis of written narrative feedback from SCAGs completed by non-standardised adolescent patients interviewed by third-year medical students. SCAG numerical scores and grades were compared between the positive and the negative written narrative feedback. RESULTS: Thirty-seven (50%) of 74 SCAGs had written narrative feedback. 'Approachable' and 'confidentiality concerns' were the most common positive and negative written comments, respectively. The 'teen-only communication' SCAG section, containing the HEADSS (Home, Education, Activities, Drugs, Suicide, Sex) portion of the interview, had the highest number of negative comments. All of the positive comments had A grades (100%), whereas the negative comments had A (58%), B (37%) and C (5%) grades. The 'teen-only communication' and 'initiating the interview' SCAG sections had significantly lower numerical scores assigned to negative feedback (p = 0.023, p < 0.001). Adolescent medical interviewing is a difficult topic to teach and assess DISCUSSION: Confidentiality concerns remain a top priority for undergraduate medical education training in adolescent patient interviewing. Written narrative feedback is extremely valuable as teens can provide both positive and negative comments. This is in contrast to adolescent patients most often over-inflating grades or scores to all learners, which can mislead the student.

Guidelines in CHARGE syndrome and the missing link: Cranial imaging.

"CHARGE syndrome" is a complex syndrome with high and extremely variable comorbidity. As a result, clinicians may struggle to provide accurate and comprehensive care, and this has led to the publication of several clinical surveillance guidelines and recommendations for CHARGE syndrome, based on both single case observations and cohort studies. Here we perform a structured literature review to examine all the existing advice. Our findings provide additional support for the validity of the recently published Trider checklist. We also identified a gap in literature when reviewing all guidelines and recommendations, and we propose a guideline for neuroradiological evaluation of patients with CHARGE syndrome. This is of importance, as patients with CHARGE are at risk for peri-anesthetic complications, making recurrent imaging procedures under anesthesia a particular risk in clinical practice. However, comprehensive cranial imaging is also of tremendous value for timely diagnosis, proper treatment of symptoms and for further research into CHARGE syndrome. We hope the guideline for neuroradiological evaluation will help clinicians provide efficient and comprehensive care for individuals with CHARGE syndrome.

Gastrointestinal and feeding difficulties in CHARGE syndrome: A review from head-to-toe.

CHARGE syndrome is an autosomal dominant genetic condition that is primarily diagnosed based on clinical features, with genetic testing available for confirmation. The CHARGE mnemonic stands for some of the common characteristics: coloboma, heart defects, atresia/stenosis of the choanae, retardation of growth/development, genitourinary anomalies, and ear abnormalities (CHARGE). However, many of the common clinical features are not captured by this mnemonic, including cranial nerve dysfunction, considered by some to be one of the major diagnostic criteria. Over 90% of individuals experience feeding and gastrointestinal dysfunction, which carries great morbidity and mortality. The aim of this review is to examine the nature of gastrointestinal (GI) symptoms and feeding difficulties in CHARGE syndrome, focusing on their underlying pathology, associated investigations, and available treatment options. We also provide information on available tools (for parents, clinicians, and researchers) that are important additions to the lifelong healthcare management of every individual with CHARGE syndrome. We review how cranial nerve dysfunction is one of the most important characteristics underlying the pervasive GI and feeding dysfunction, and discuss the need for future research on gut innervation and motility in this genetic disorder.

Experiences in feeding and gastrointestinal dysfunction in children with CHARGE syndrome.

Feeding issues are very common in individuals with CHARGE syndrome and can lead to increased morbidity and mortality. The aim of this study was to expand upon the limited knowledge base of feeding and gastrointestinal issues in individuals with CHARGE syndrome. Parents of individuals (age range 1-18 years) with CHARGE syndrome, with or without feeding/gastrointestinal issues, were recruited through international CHARGE syndrome associations and CHARGE syndrome Facebook pages. Parents completed three questionnaires: CHARGE diagnostic characteristics; Pediatric Assessment Scale for Severe Feeding Problems © and PedsQL™ Gastrointestinal Symptoms Scale; and open-ended questions. Sixty-nine completed questionnaires were included in the study analysis (median age 7; 58% females). Individuals who were completely tube fed (n = 21) had significantly more feeding difficulties than individuals who were either partially (n = 26) or completely orally fed (n = 20; p < 0.001). Tube fed individuals also experienced more problematic gastrointestinal symptoms (p < 0.001). Constipation (n = 19, 30%), vomiting (n = 12, 19%), and choking (n = 11, 17%) were reported by parents as the greatest challenges. Problems exist throughout the entire gastrointestinal tract in many individuals with CHARGE syndrome. These issues are more common in individuals who receive nutrition completely through a feeding tube compared to individuals with at least partial oral feeding behaviors.

Developing a CHARGE syndrome checklist: Health supervision across the lifespan (from head to toe).

Health supervision and management considerations for individuals with CHARGE syndrome are often complex, and a comprehensive approach is essential. The Atlantic Canadian CHARGE syndrome team developed a checklist organized by body system and age to aid healthcare providers in their approach to the ongoing care of these individuals. The checklist was evaluated qualitatively using a modified Delphi method with widespread consultation from expert healthcare practitioners, parents, and individuals with CHARGE syndrome. These are the first comprehensive guidelines across the lifespan of CHARGE syndrome that suggest a consistent approach to medical surveillance, investigations, and management for the physician and the multi-disciplinary team caring for these individuals. We anticipate that these guidelines will provide improvements in care by preventing missed diagnoses, allowing for anticipatory counseling, and facilitating early referral for interventions and treatments. © 2017 Wiley Periodicals, Inc.

Skills for Interviewing Adolescent Patients: Sustainability of Structured Feedback in Undergraduate Education on Performance in Residency.

BACKGROUND: Effective adolescent (10 to 19 years) interviewing by physicians is an essential skill that many trainees can find challenging. OBJECTIVE: We assessed whether structured adolescent interviewing using standardized patients (SPs) and feedback in undergraduate medical education (UME) has a sustained effect on residents' skills. METHODS: Postgraduate year (PGY) 1 residents conducted interviews with a SP adolescent-mother pair. The SPs independently scored each PGY-1 interview using the structured communication adolescent guide (SCAG). Unpaired t tests were conducted comparing "Total-Item" and "Global" scores of PGY-1s who received structured SP adolescent interviewing with feedback in UME ("structured training" group) to those who had not ("no structured training" group). RESULTS: PGY-1s in the structured training group (n = 23) received significantly higher mean Total-Item scores from both the SP adolescent (40.78 ± 7.04 and 32.41 ± 10.12, respectively; P = .001) and the SP mother (40.48 ± 7.90 and 33.34 ± 10.90, respectively; P = .01) than those without structured training (n = 29). Statistically significant results favoring PGY-1s with prior training were also seen with the SP adolescent and mother total Global SCAG scores. CONCLUSIONS: Structured training in adolescent interviewing with SPs and feedback in UME appears to have a sustained effect on residents' adolescent interviewing skills. PGY-1s will interview adolescents and may benefit from structured adolescent SP interviewing with feedback, especially individuals who did not have this experience during their medical school training.

Quality of life in adolescents and adults with CHARGE syndrome.

Health-related Quality of Life and the Impact of Childhood Neurologic Disability Scale were collected for 53 patients with CHARGE syndrome aged 13-39 years with a mean academic level of 4th grade. The most prevalent new and ongoing issues included bone health issues, sleep apnea, retinal detachment, anxiety, and aggression. Sleep issues were significantly correlated with anxiety, self-abuse, conduct problems, and autistic-like behaviors. Problems with overall health, behavior, and balance most affected the number of social activities in the individual's life. Sensory impairment most affected relationships with friends. Two contrasting case studies are presented and demonstrate that the quality of life exists on a broad spectrum in CHARGE syndrome, just as its physical features range from mild to very severe. A multitude of factors, including those beyond the physical manifestations, such as anxiety and sleep problems, influence quality of life and are important areas for intervention. © 2016 Wiley Periodicals, Inc.