Whole-exome sequencing in syndromic craniosynostosis increases diagnostic yield and identifies candidate genes in osteogenic signaling pathways.

Craniosynostosis (CS) is a common congenital anomaly defined by premature fusion of one or more cranial sutures. Syndromic CS involves additional organ anomalies or neurocognitive deficits and accounts for 25%-30% of the cases. In a recent population-based study by our group, 84% of the syndromic CS cases had a genetically verified diagnosis after targeted analyses. A number of different genetic causes were detected, confirming that syndromic CS is highly heterogeneous. In this study, we performed whole-exome sequencing of 10 children and parents from the same cohort where previous genetic results were negative. We detected pathogenic, or likely pathogenic, variants in four additional genes (NFIA, EXTL3, POLR2A, and FOXP2) associated with rare conditions. In two of these (POLR2A and FOXP2), CS has not previously been reported. We further detected a rare predicted damaging variant in SH3BP4, which has not previously been related to human disease. All findings were clustered in genes involved in the pathways of osteogenesis and suture patency. We conclude that whole-exome sequencing expands the list of genes associated with syndromic CS, and provides new candidate genes in osteogenic signaling pathways.

Living with orofacial conditions: psychological distress and quality of life in adults affected with Treacher Collins syndrome, cherubism, or oligodontia/ectodermal dysplasia-a comparative study.

PURPOSE: The relationship between quality of life, psychological distress, and orofacial syndromes in children and adolescents has been reported in several studies. However, little is known about differences in psychological distress and quality of life among adults with different orofacial conditions. Therefore, the aims of this study were to examine and compare these factors among three groups of adults affected by Treacher Collins syndrome (TCS), cherubism, and oligodontia/ectodermal dysplasia (ED). METHODS: We included 11 individuals with TCS (mean age 46.9, SD 12.9 years), 15 with cherubism (mean age 50.3, SD 16.8 years), and 49 with oligodontia/ED (mean age 30.7, SD 15.6 years). The respondents completed questionnaires related to psychological distress and quality of life. RESULTS: The oligodontia/ED group had a significantly higher level of anxiety and worse mental health-related quality of life than both the TCS and cherubism groups. Adults with TCS reported the highest level of depression, and the lowest levels of overall quality of life, well-being, and physical health-related quality of life. The cherubism group displayed the best overall quality of life, well-being, and mental health. CONCLUSIONS: Psychological distress and quality of life differed in various orofacial conditions. This study provided insight into these aspects that may contribute to improved care.

Profiles of orofacial dysfunction in different diagnostic groups using the Nordic Orofacial Test (NOT-S)--a review.

OBJECTIVE: The Nordic Orofacial Test-Screening (NOT-S) was developed as a comprehensive method to assess orofacial function. Results from the screening protocol have been presented in 11 international publications to date. This study reviewed these publications in order to compile NOT-S screening data and create profiles of orofacial dysfunction that characterize various age groups and disorders. MATERIALS AND METHODS: NOT-S results of nine reports meeting the inclusion criteria were reviewed. Seven of these studies not only provided data on the mean and range of total NOT-S scores, but also on the most common domains of orofacial dysfunction (highest rate of individuals with dysfunction scores), allowing the construction of orofacial dysfunction profiles based on the prevalence of dysfunction in each domain of NOT-S. RESULTS: The compiled data comprised 669 individuals, which included healthy control subjects (n = 333) and various patient groups (n = 336). All studies reported differences between individuals with diagnosed disorders and healthy control subjects. The NOT-S data could measure treatment effects and provided dysfunction profiles characterizing the patterns of orofacial dysfunction in various diagnoses. CONCLUSIONS: This review corroborates previous results that the NOT-S differentiates well between patients and healthy controls and can also show changes in individuals after treatment. NOT-S could be used as a standard instrument to assess orofacial dysfunction, evaluate the outcomes of oral habilitation and rehabilitation and improve comparability in clinical practice and research.

Associations between speech features and phenotypic severity in Treacher Collins syndrome.

BACKGROUND: Treacher Collins syndrome (TCS, OMIM 154500) is a rare congenital disorder of craniofacial development. Characteristic hypoplastic malformations of the ears, zygomatic arch, mandible and pharynx have been described in detail. However, reports on the impact of these malformations on speech are few. Exploring speech features and investigating if speech function is related to phenotypic severity are essential for optimizing follow-up and treatment. METHODS: Articulation, nasal resonance, voice and intelligibility were examined in 19 individuals (5-74 years, median 34 years) divided into three groups comprising children 5-10 years (n = 4), adolescents 11-18 years (n = 4) and adults 29 years and older (n = 11). A speech composite score (0-6) was calculated to reflect the variability of speech deviations. TCS severity scores of phenotypic expression and total scores of Nordic Orofacial Test-Screening (NOT-S) measuring orofacial dysfunction were used in analyses of correlation with speech characteristics (speech composite scores). RESULTS: Children and adolescents presented with significantly higher speech composite scores (median 4, range 1-6) than adults (median 1, range 0-5). Nearly all children and adolescents (6/8) displayed speech deviations of articulation, nasal resonance and voice, while only three adults were identified with multiple speech aberrations. The variability of speech dysfunction in TCS was exhibited by individual combinations of speech deviations in 13/19 participants. The speech composite scores correlated with TCS severity scores and NOT-S total scores. Speech composite scores higher than 4 were associated with cleft palate. The percent of intelligible words in connected speech was significantly lower in children and adolescents (median 77%, range 31-99) than in adults (98%, range 93-100). Intelligibility of speech among the children was markedly inconsistent and clearly affecting the understandability. CONCLUSIONS: Multiple speech deviations were identified in children, adolescents and a subgroup of adults with TCS. Only children displayed markedly reduced intelligibility. Speech was significantly correlated with phenotypic severity of TCS and orofacial dysfunction. Follow-up and treatment of speech should still be focused on young patients, but some adults with TCS seem to require continuing speech and language pathology services.

Association between obstructive sleep apnea and health-related quality of life in individuals affected with Treacher Collins syndrome.

Although the relationship between Quality of Life (QoL) and obstructive sleep apnea (OSA) has been reported in several studies, little is known about this relationship among individuals affected with Treacher Collins syndrome (TCS). The aim of this study was to examine the associations between obstructive sleep and QoL in TCS patients. Thirty-six individuals with TCS (8-75 years) were invited to participate in expanded medical examinations, including a sleep study, polysomnography, as well as to respond to questionnaires about health related Health-related quality of life (HRQoL). Twenty-three (64 %) responded to the invitation, but four were later excluded due to additional diagnoses or unconfirmed TCS, and four were below 12 years and excluded due to different scoring rules for sleep and respiratory disturbances in young children and adults. The remaining group comprised 15 adults and adolescents with TCS, 5 male (33 %) and 10 female (66 %). The participants were between 12 and 75 years of age (mean 38.6, SD 18.5). Obstructive sleep was found in 87 % of the patients and several sleep apnea parameters, among these wake time after sleep, subjective snoring and mean saturation, were associated with poorer HRQoL. OSA appears to account for reduced HRQoL in adolescents and adults with TCS.

Orofacial functions and oral health associated with Treacher Collins syndrome.

OBJECTIVE: The aim of this study was to describe orofacial features and functions and oral health associated with Treacher Collins syndrome (TCS) in relation to the variable phenotypic expression of the condition. MATERIALS AND METHODS: The Nordic Orofacial Test-Screening (NOT-S), MHC Questionnaire, MHC Observation chart and clinical examinations of nasal and pharyngeal conditions and chewing and swallowing function were used to assess 19 individuals aged 5-74 years (median 34 years). TCS severity scores were calculated by a clinical geneticist. RESULTS: Orofacial features characterizing the study group were altered profile, increased mandibular angle, narrow hypopharynx and facial asymmetry. Basic orofacial functions such as breathing, eating, facial expression and speech were affected in all subjects demonstrating orofacial dysfunction in at least two NOT-S domains (median NOT-S total score 4/12, range 2-7). Significant correlation was found between the TCS severity scores reflecting phenotypic expression and the NOT-S total scores reflecting orofacial function. Self-reported experience of dry oral mucosa was common. Overall, dental health was good with few carious lesions diagnosed, but considerable need for orthodontic treatment was documented. CONCLUSIONS: Altered orofacial features and functions in TCS are common and often persist into late adolescence and adulthood. The functional level was correlated with the phenotypic variability of the condition. The standard of oral health was satisfactory. The findings indicated that individuals with TCS are likely to require lifelong health services related to their oral condition.

Salivary gland pathology as a new finding in Treacher Collins syndrome.

In our clinical experience, individuals with Treacher Collins syndrome (TCS) present with more complaints of oral dryness and higher caries activity than seen in the general population. A literature review identified no reports of salivary gland pathology and glandular dysfunction associated with TCS. Twenty-one Norwegian individuals with TCS underwent ultrasound examinations and salivary secretion tests of the submandibular and parotid glands. Intraglandular architecture patterns were analyzed and subsequently classified as either normal, dysplastic, or aplastic. The results were compared with salivary secretion rates and subjective reports of oral dryness. Ultrasound examination revealed pathological appearance of the salivary glands in approximately half (48%) of the individuals, with dysplasia identified in six (29%) participants and aplasia in four (19%). Almost all participants had co-existing low salivary secretion rates. A few individuals had low salivary secretion rates despite normal appearance of the salivary gland tissue on ultrasound examination. Subjective experience of oral dryness did not correlate significantly with low salivary secretion rates. We conclude that mild to severe salivary gland pathology and dysfunction can be associated with TCS. Further investigation is needed to clarify this association.

Drooling: are botulinum toxin injections into the major salivary glands a good treatment option?

There are several treatment options available for drooling; botulinum toxin injections into the major salivary glands are one. There is no consensus as to how many and which glands should be injected. A research project on this topic was terminated because of adverse effects. Individual results and the adverse effects are described and discussed in this article. Six individuals with cerebral palsy were randomly allocated to 2 treatment groups, with five individuals receiving ultrasound-guided injections to parotid and submandibular glands and one receiving injections to the submandibular glands only. Reduction of observed drooling was registered in 3, while 4 patients reported subjective improvement (Visual Analog Scale). Two participants reported adverse effects, including dysphagia, dysarthria, and increased salivary viscosity. Injections with botulinum toxin can be a useful treatment option but there is a risk of adverse effects. Multidisciplinary evaluation and informed discussions with patients/caregivers are important factors in the decision-making process.

Obstructive sleep apnea in Treacher Collins syndrome.

The aim of the present study was to investigate the prevalence of obstructive sleep apnea syndrome (OSAS) among the Norwegian population with Treacher Collins syndrome (TCS). A secondary aim was to establish whether TCS phenotype severity is associated with OSAS severity. A prospective case study design was used. Individuals who were 5 years old and above with a known diagnosis of TCS in Norway were invited to participate in a study. The study included genetic testing, medical and dental examinations and polysomnography. All participants demonstrated disturbed respiration during sleep; 18/19 met the diagnostic criteria for OSAS. Subjectively evaluated snoring was not a reliable predictor of OSAS. We found no significant association between TCS phenotype severity and the severity of OSAS. OSAS is common in TCS, but there is no association with the phenotype severity. Individuals diagnosed with TCS must undergo sleep studies to identify the presence of OSAS.

Orofacial dysfunction in individuals with Prader-Willi syndrome assessed with NOT-S.

OBJECTIVE: The objective of the study was to evaluate orofacial dysfunction in individuals with Prader-Willi syndrome (PWS) and compare it with a healthy reference group. METHODS AND MATERIALS: The Nordic Orofacial Test-Screening (NOT-S) protocol was used for evaluation of orofacial function in 45 (23 Male, 22 Female) individuals with PWS, aged 19.8 ± 9.5 years, and a reference group of 40 (18 M, 22 F) healthy individuals, aged 24.0 ± 16.3 years. RESULTS: The NOT-S score was markedly higher for the individuals with PWS than for the healthy reference group (3.9 ± 2.1 vs 0.3 ± 0.5, p < 0.001). The most common domains of dysfunction in individuals with PWS were Oral motor function (60.0%), Habits (55.6%), Face at rest (53.3%), Speech (44.4%), Drooling (44.4%) and Breathing (42.2%). CONCLUSIONS: Eighty-seven per cent of the participants with PWS demonstrated dysfunction in two or more domains, particularly in the domains Oral motor function, Habits and Face at rest.

Development and evaluation of a comprehensive screening for orofacial dysfunction.

The aim was to develop a comprehensive screening instrument for evaluation of orofacial dysfunction that was easy to perform for different health professionals without special equipment. The Nordic Orofacial Test--Screening (NOT-S), consisting of a structured interview and clinical examination,was developed with a picture manual illustrating the different tasks in the examination. It was first tested in a Swedish version, and later translated to other Nordic languages, and to English. The interview reflected six domains, (I) Sensory function, (II) Breathing, (III) Habits, (IV) Chewing and swallowing, (V) Drooling, and (VI) Dryness of the mouth, and the examination included six domains representing (1) The face at rest, and tasks regarding (2) Nose breathing, (3) Facial expression, (4) Masticatory muscle and jaw function, (5) Oral motor function, and (6) Speech. One or more "yes" for impairment in a domain resulted in one point (maximum NOT-S score 12 points). The mean NOT-S score (+/- SD) in 120 patients (3-86 yr), referred to five centers for specialized dental care or speech and language pathology in Sweden, Norway and Denmark, was 4.1 +/- 2.6, and 0.4 +/- 0.6 in 60 control subjects (3-78 yr). The screening was easy to administer and the time spent 5-13 min. The scores from the clinic-referred sample differed significantly from the controls, and the sensitivity of the screening was 0.96 and specificity 0.63. Repeated evaluations of videotapes of 200 patients by 3 examiners, speech-language pathologists and dentists, with at least two-week intervals, showed inter- and intraexaminer agreement on the points given in the domains at respectively 83% and 92-95% which increased after recalibration to 85% and 95-99%. Kappa values for interexaminer agreement on the NOT-S scores were 0.42-0.44 (i.e. fair), and the method error was 5.3%. To conclude, NOT-S gave a reliable and valid screening for orofacial dysfunction.