Brain volume in infants with metopic synostosis: Less white matter volume with an accelerated growth pattern in early life.

Metopic synostosis patients are at risk for neurodevelopmental disorders despite a negligible risk of intracranial hypertension. To gain insight into the underlying pathophysiology of metopic synostosis and associated neurodevelopmental disorders, we aimed to investigate brain volumes of non-syndromic metopic synostosis patients using preoperative MRI brain scans. MRI brain scans were processed with HyperDenseNet to calculate total intracranial volume (TIV), total brain volume (TBV), total grey matter volume (TGMV), total white matter volume (TWMV) and total cerebrospinal fluid volume (TCBFV). We compared global brain volumes of patients with controls corrected for age and sex using linear regression. Lobe-specific grey matter volumes were assessed in secondary analyses. We included 45 metopic synostosis patients and 14 controls (median age at MRI 0.56 years [IQR 0.36] and 1.1 years [IQR 0.47], respectively). We found no significant differences in TIV, TBV, TGMV or TCBFV in patients compared to controls. TWMV was significantly smaller in patients (-62,233 mm3 [95% CI = -96,968; -27,498], Holm-corrected p = 0.004), and raw data show an accelerated growth pattern of white matter in metopic synostosis patients. Grey matter volume analyses per lobe indicated increased cingulate (1378 mm3 [95% CI = 402; 2355]) and temporal grey matter (4747 [95% CI = 178; 9317]) volumes in patients compared to controls. To conclude, we found smaller TWMV with an accelerated white matter growth pattern in metopic synostosis patients, similar to white matter growth patterns seen in autism. TIV, TBV, TGMV and TCBFV were comparable in patients and controls. Secondary analyses suggest larger cingulate and temporal lobe volumes. These findings suggest a generalized intrinsic brain anomaly in the pathophysiology of neurodevelopmental disorders associated with metopic synostosis.

Quality of life in children suffering from headaches: a systematic literature review.

BACKGROUND: Headaches are the most common complaints among pediatric populations. Determining the cause and appropriate treatment for headaches may be challenging and costly, and the impact of headaches on the lives of patients and their families is not well understood. OBJECTIVE: A systematic literature review was conducted to examine what PROMs are currently used, and to identify quality of life (QoL) concepts important to children suffering from headaches and any known determinants of QoL. METHODS: Embase, Medline, Web of Science, CINAHL, EBSCOhost, PsychINFO, Cochrane CENTRAL and Google Scholar were searched from their inception through to June 2021. Studies investigating QoL, using a validated outcome measure in pediatric patients with headaches, were included. Relevant studies were identified through title and abstract screening and full text review by two independent reviewers. A citation review of included studies was performed. QoL concepts were extracted from the outcome measures that were used in each study to develop a preliminary conceptual model of QoL in children suffering from headaches. Determinants of QoL were also identified and categorized. RESULTS: A total of 5421 studies were identified in the search. Title and abstract screening resulted in the exclusion of 5006 studies. Among the 415 studies included for full text review, 56 were eligible for final analysis. A citation review resulted in the addition of five studies. Most studies were conducted in high-income countries and included a patient-sample accordingly (n = 45 studies). Sixteen different PROMs were identified in the included studies, of which the PedsQL was used the most often (n = 38 studies). The most common health concepts reported were physical functioning (n = 113 items), social and psychological wellbeing (N = 117, n = 91 resp.). Twenty-five unique determinants of QoL were extracted from the included studies. CONCLUSION: There is a need for a condition-specific PROM to facilitate the measurement of QoL outcomes in the pediatric headache population. A conceptual model was developed based on the findings from the health concepts. Findings from this review could be used for future qualitative interviews with pediatric patients with headaches to elicit and refine important QoL concepts.

A diffusion tensor imaging analysis of white matter microstructures in non-operated craniosynostosis patients.

PURPOSE: In 7 to 15-year-old operated syndromic craniosynostosis patients, we have shown the presence of microstructural anomalies in brain white matter by using DTI. To learn more about the cause of these anomalies, the aim of the study is to determine diffusivity values in white matter tracts in non-operated syndromic craniosynostosis patients aged 0-2 years compared to healthy controls. METHODS: DTI datasets of 51 non-operated patients with syndromic craniosynostosis with a median [IQR] age of 0.40 [0.25] years were compared with 17 control subjects with a median of 1.20 [0.85] years. Major white matter tract pathways were reconstructed with ExploreDTI from MRI brain datasets acquired on a 1.5 T MRI system. Eigenvalues of these tract data were examined, with subsequent assessment of the affected tracts. Having syndromic craniosynostosis (versus control), gender, age, frontal occipital horn ratio (FOHR), and tract volume were treated as independent variables. RESULTS: ʎ2 and ʎ3 of the tracts genu of the corpus callosum and the hippocampal segment of the cingulum bundle show a ƞ2 > 0.14 in the comparison of patients vs controls, which indicates a large effect on radial diffusivity. Subsequent linear regressions on radial diffusivity of these tracts show that age and FOHR are significantly associated interacting factors on radial diffusivity (p < 0.025). CONCLUSION: Syndromic craniosynostosis shows not to be a significant factor influencing the major white matter tracts. Enlargement of the ventricles show to be a significant factor on radial diffusivity in the tracts corpus callosum genu and the hippocampal segment of the cingulate bundle. CLINICAL TRIAL REGISTRATION: MEC-2014-461.

The impact of obstructive sleep apnea on growth in patients with syndromic and complex craniosynostosis: a retrospective study.

Given the high prevalence of OSA in children with syndromic and complex craniosynostosis (SCC) and the consequences of untreated OSA, it is important to assess their nutritional status and growth. Yet, literature regarding growth in children with SCC remain scarce. Therefore, this study aimed to (1) illustrate the growth pattern in SCC, (2) determine the impact of OSA on this growth pattern, and (3) evaluate the effect of surgical treatment of OSA on growth over time. A retrospective study was performed in children with SCC, who were treated at the Dutch Craniofacial Center (Rotterdam, Netherlands). Growth variables (height, weight, weight-for-age standard-deviation-score (SDS), weight-for-height SDS, and height-for-age SDS) and degree of OSA (obstructive apnea-hypopnea index) were assessed. Of the 153 children with SCC, 38 (25%) were acutely malnourished at some point during follow-up, of whom 21 had disease-related acute malnutrition. Children with moderate-severe OSA had significant lower weight-for-height SDS compared to children without OSA (p = 0.0063). Growth parameters (weight-for-age SDS, weight-for-height SDS, height-for-age SDS) in children with SCC without OSA were not impaired as they did not differ from the normal healthy population, with exception of the patients with Saethre-Chotzen syndrome (SCS) who had a significantly lower SDS for height-for-age.   Conclusion: Children with SCC have a substantial chance of developing acute malnutrition at some point during growth. Additionally, in children with moderate-severe OSA, a significant lower SDS for weight-for-height is present, indicating the importance of assessing the weight and growth pattern in children who are clinically suspected for OSA. What is Known: • Obstructive sleep apnea is seen in up to two-thirds of the children with syndromic and complex craniosynostosis. • Presence of obstructive sleep apnea is associated with intracranial hypertension and an increased risk of metabolic, cardiovascular, and neurocognitive consequences later in life. Untreated obstructive sleep apnea may lead to impaired growth and weight gain, which can result in growth failure. What is New: • Craniosynostosis patients with moderate-severe obstructive sleep apnea had significant lower weight-for-height standard deviation scores (SDS), compared to children without obstructive sleep apnea.  • Children with syndromic and complex craniosynostosis without OSA did not significantly differ from the normal healthy population in regard to weight-for-age SDS, weight-for-height SDS, and height-for-age SDS.

Craniofacial morphology and growth in Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis.

OBJECTIVES: To determine whether the midface of patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis is hypoplastic compared to skeletal facial proportions of a Dutch control group. MATERIAL AND METHODS: We included seventy-four patients (43 patients with Muenke syndrome, 22 patients with Saethre-Chotzen syndrome, and 9 patients with TCF12-related craniosynostosis) who were referred between 1990 and 2020 (age range 4.84 to 16.83 years) and were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care and Orthodontics, Children's Hospital Erasmus University Medical Center, Sophia, Rotterdam, the Netherlands. The control group consisted of 208 healthy children. RESULTS: Cephalometric values comprising the midface were decreased in Muenke syndrome (ANB: ß = -1.87, p = 0.001; and PC1: p < 0,001), Saethre-Chotzen syndrome (ANB: ß = -1.76, p = 0.001; and PC1: p < 0.001), and TCF12-related craniosynostosis (ANB: ß = -1.70, p = 0.015; and PC1: p < 0.033). CONCLUSIONS: In this study, we showed that the midface is hypoplastic in Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis compared to the Dutch control group. Furthermore, the rotation of the maxilla and the typical craniofacial buildup is significantly different in these three craniosynostosis syndromes compared to the controls. CLINICAL RELEVANCE: The maxillary growth in patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis is impaired, leading to a deviant dental development. Therefore, timely orthodontic follow-up is recommended. In order to increase expertise and support treatment planning by medical and dental specialists for these patients, and also because of the specific differences between the syndromes, we recommend the management of patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis in specialized multidisciplinary teams.

Bi-allelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes.

STUDY QUESTION: Do bi-allelic variants in the genes encoding the MSH4/MSH5 heterodimer cause male infertility? SUMMARY ANSWER: We detected biallelic, (likely) pathogenic variants in MSH5 (4 men) and MSH4 (3 men) in six azoospermic men, demonstrating that genetic variants in these genes are a relevant cause of male infertility. WHAT IS KNOWN ALREADY: MSH4 and MSH5 form a heterodimer, which is required for prophase of meiosis I. One variant in MSH5 and two variants in MSH4 have been described as causal for premature ovarian insufficiency (POI) in a total of five women, resulting in infertility. Recently, pathogenic variants in MSH4 have been reported in infertile men. So far, no pathogenic variants in MSH5 had been described in males. STUDY DESIGN, SIZE, DURATION: We utilized exome data from 1305 men included in the Male Reproductive Genomics (MERGE) study, including 90 males with meiotic arrest (MeiA). Independently, exome sequencing was performed in a man with MeiA from a large consanguineous family. PARTICIPANTS/MATERIALS, SETTING, METHODS: Assuming an autosomal-recessive mode of inheritance, we screened the exome data for rare, biallelic coding variants in MSH4 and MSH5. If possible, segregation analysis in the patients' families was performed. The functional consequences of identified loss-of-function (LoF) variants in MSH5 were studied using heterologous expression of the MSH5 protein in HEK293T cells. The point of arrest during meiosis was determined by γH2AX staining. MAIN RESULTS AND THE ROLE OF CHANCE: We report for the first time (likely) pathogenic, homozygous variants in MSH5 causing infertility in 2 out of 90 men with MeiA and overall in 4 out of 902 azoospermic men. Additionally, we detected biallelic variants in MSH4 in two men with MeiA and in the sister of one proband with POI. γH2AX staining revealed an arrest in early prophase of meiosis I in individuals with pathogenic MSH4 or MSH5 variants. Heterologous in vitro expression of the detected LoF variants in MSH5 showed that the variant p.(Ala620GlnTer9) resulted in MSH5 protein truncation and the variant p.(Ser26GlnfsTer42) resulted in a complete loss of MSH5. LARGE SCALE DATA: All variants have been submitted to ClinVar (SCV001468891-SCV001468896 and SCV001591030) and can also be accessed in the Male Fertility Gene Atlas (MFGA). LIMITATIONS, REASONS FOR CAUTION: By selecting for variants in MSH4 and MSH5, we were able to determine the cause of infertility in six men and one woman, leaving most of the examined individuals without a causal diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: Our findings have diagnostic value by increasing the number of genes associated with non-obstructive azoospermia with high clinical validity. The analysis of such genes has prognostic consequences for assessing whether men with azoospermia would benefit from a testicular biopsy. We also provide further evidence that MeiA in men and POI in women share the same genetic causes. STUDY FUNDING/COMPETING INTEREST(S): This study was carried out within the frame of the German Research Foundation sponsored Clinical Research Unit 'Male Germ Cells: from Genes to Function' (DFG, CRU326), and supported by institutional funding of the Research Institute Amsterdam Reproduction and Development and funds from the LucaBella Foundation. The authors declare no conflict of interest.

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

Deviating dental arch morphology in mild coronal craniosynostosis syndromes.

OBJECTIVES: To determine whether the intramaxillary relationship of patients with Muenke syndrome and Saethre-Chotzen syndrome or TCF12-related craniosynostosis are systematically different than those of a control group. MATERIAL AND METHODS: Forty-eight patients (34 patients with Muenke syndrome, 8 patients with Saethre-Chotzen syndrome, and 6 patients with TCF12-related craniosynostosis) born between 1982 and 2010 (age range 4.84 to 16.83 years) that were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care and Orthodontics, Children's Hospital Erasmus University Medical Center, Sophia, Rotterdam, the Netherlands, were included. Forty-seven syndromic patients had undergone one craniofacial surgery according to the craniofacial team protocol. The dental arch measurements intercanine width (ICW), intermolar width (IMW), arch depth (AD), and arch length (AL) were calculated. The control group existed of 329 nonsyndromic children. RESULTS: All dental arch dimensions in Muenke (ICW, IMW, AL, p < 0.001, ADmax, p = 0.008; ADman, p = 0.002), Saethre-Chotzen syndrome, or TCF12-related craniosynostosis patients (ICWmax, p = 0.005; ICWman, IMWmax, AL, p < 0.001) were statistically significantly smaller than those of the control group. CONCLUSIONS: In this study, we showed that the dental arches of the maxilla and the mandible of patients with Muenke syndrome and Saethre-Chotzen syndrome or TCF12-related craniosynostosis are smaller compared to those of a control group. CLINICAL RELEVANCE: To gain better understanding of the sutural involvement in the midface and support treatment capabilities of medical and dental specialists in these patients, we suggest the concentration of patients with Muenke and Saethre-Chotzen syndromes or TCF12-related craniosynostosis in specialized teams for a multi-disciplinary approach and treatment.

Atypical presentation of a newborn with Apert syndrome.

INTRODUCTION: Apert syndrome is a rare syndrome characterized by a consistent phenotype including bilateral coronal suture synostosis with an enlarged anterior fontanel, midface hypoplasia, and complex symmetric syndactyly of hands and feet. CASE REPORT: We present a boy with Apert syndrome caused by the pathogenic c.755C > G p.Ser252Trp mutation in the FGFR2 gene with atypical characteristics, including premature fusion of the metopic suture with a small anterior fontanel, hypotelorism, and a massive posterior fontanel. Directly after birth, he showed papilledema, epilepsy, and central apneas. CONCLUSION: We present a newborn with Apert syndrome with atypical craniofacial presentation.

Comparison of two surgical protocols for the treatment of unilateral cleft lip and palate: a multidisciplinary systematic review and meta-analysis.

There is still no unanimous agreement on the optimal surgical protocol(s) for the treatment of unilateral cleft lip and palate (UCLP), and a huge variety of protocols are employed by cleft centres across the world. The aim of this systematic review and meta-analysis was to compare reported patient outcomes of the Oslo protocol (and modifications) (OP) and delayed hard palate closure protocols (DHPCP) from a multidisciplinary perspective. A systematic search of multiple databases was conducted until September 2023. Studies reporting any patient outcomes of these protocols were included. Random-effects meta-analyses were performed for evidence synthesis, including comparisons of results between the types of protocol. The quality of evidence was evaluated using the ROBINS-I tool. In total, 62 articles (42 studies) reporting patients with UCLP were reviewed, involving 1281 patients following the OP and 655 following DHPCP. Equally poor long-term sagittal maxillofacial growth was found, and similar results for velopharyngeal insufficiency and nasolabial appearance. In contrast, OP was associated with a lower rate of oronasal fistulas. Disregarding the scarcity of comparable evidence for some domains, the results of this review, overall, favour OP over DHPCP. However, caution should be taken when interpreting the results on velopharyngeal insufficiency and oronasal fistulas, since the possibility of confounding and other biases remains.

Spring-assisted posterior vault expansion in multisuture craniosynostosis.

PURPOSE: Patients with Apert and Crouzon syndromes and craniofrontonasal dysplasia need a vault expansion within the first year of life to treat or prevent the development of raised intracranial pressure. Many craniofacial units perform a conventional posterior vault expansion as initial surgery; an alternative to this technique is the spring-assisted posterior vault expansion. The purpose of this study was to demonstrate the efficacy of spring-assisted posterior vault expansion and to compare this technique with the conventional method. METHODS: A retrospective study was conducted among all consecutive patients who received a posterior vault expansion between 2006 and 2011. Patients treated with springs were compared with patients treated with the conventional technique for blood loss, duration of surgery, postoperative hospital admittance, increase in skull circumference and anterior-posterior length, and complications. RESULTS: Of the 31 included patients, 15 were treated with springs, and 16, with the conventional technique. Patients treated with springs had a significantly larger increase in skull circumference and anterior-posterior length, and not significant changes in blood loss compared with the conventional group. Complications in the conventional group were the following: minor dural tear in three patients, problematic wound healing in one patient, and insufficient expansion in one patient. Spring-related complications included skin perforation in two patients, a minor dural tear in two patients, and leakage of cerebrospinal fluid after an unnoticed dural tear during spring placement in one patient. CONCLUSION: Spring-assisted posterior vault expansion has some advantages over the conventional technique and is, therefore, the preferred technique in our center.

Sphenoid dysplasia in patients with neurofibromatosis type 1: Clinical features and imaging findings including cerebrospinal fluid alterations.

INTRODUCTION: Neurofibromatosis Type 1 (NF-1) is a genetic disorder that occurs in 1:2500-3000 live births and may involve multiple organs. An uncommon but well-known phenomena is sphenoid dysplasia, which appears in 3-11% of the patients, and may result in significant lowering of the orbit. Understanding the cause and development of this process might predict its course and its treatment. METHODS: The records of 29 patients with PNF in the head and neck region were searched for location of the PNF and type of surgery. Photographs were studied for facial disturbances, including vertical dystopia, hypertelorism, ptosis, exophthalmos and enophthalmos. MR and CT scans were studied for the presence of PNF, aspect of the sphenoid bone, alteration in the CSF circulation, and other tumour involvement. RESULTS: Fourteen of 29 patients with PNF in the head and neck presented with sphenoid dysplasia. All 14 patients had their PNF located in the periorbital region. Increased locoregional CSF collections were seen in almost all of these patients. Besides glioma of the optical nerve or hamartomas in the cerebrum and cerebellum, there were no other tumours found. Surgical treatment varies from simple excision to excessive debulking of the PNF, reconstruction of the orbit and even enucleation. CONCLUSION: Although sphenoid dysplasia is uncommon in NF-1 patients, early recognition is important to prevent facial disfigurement and vision loss. Clinicians should be aware that abnormalities in the periorbital region and especially vertical dystopia might be the first sign of sphenoid dysplasia. Performing a CT or black-bone MR scan would be the next step to confirm or exclude sphenoid dysplasia and abnormal CSF dynamics.

Brain and ventricular volume in patients with syndromic and complex craniosynostosis.

PURPOSE: Brain abnormalities in patients with syndromic craniosynostosis can either be a direct result of the genetic defect or develop secondary to compression due to craniosynostosis, raised ICP or hydrocephalus. Today it is unknown whether children with syndromic craniosynostosis have normal brain volumes. The purpose of this study was to evaluate brain and ventricular volume measurements in patients with syndromic and complex craniosynostosis. This knowledge will improve our understanding of brain development and the origin of raised intracranial pressure in syndromic craniosynostosis. METHODS: Brain and ventricular volumes were calculated from MRI scans of patients with craniosynostosis, 0.3 to 18.3 years of age. Brain volume was compared to age matched controls from the literature. All patient charts were reviewed to look for possible predictors of brain and ventricular volume. RESULTS: Total brain volume in syndromic craniosynostosis equals that of normal controls, in the age range of 1 to 12 years. Brain growth occurred particularly in the first 5 years of age, after which it stabilized. Within the studied population, ventricular volume was significantly larger in Apert syndrome compared to all other syndromes and in patients with a Chiari I malformation. CONCLUSIONS: Patients with syndromic craniosynostosis have a normal total brain volume compared to normal controls. Increased ventricular volume is associated with Apert syndrome and Chiari I malformations, which is most commonly found in Crouzon syndrome. We advice screening of all patients with Apert and Crouzon syndrome for the development of enlarged ventricle volume and the presence of a Chiari I malformation.

Acceptability and feasibility of an online psychosocial intervention for Dutch adolescents with a visible difference: A mixed-methods study.

Adolescents with a visible difference can experience difficult social situations, (e.g., people staring or making unwanted comments) and are at risk for mental health problems. Unfortunately, interventions for adolescents with a visible difference experiencing appearance-related distress are scarce and lack an evidence-base. This study tests the acceptability and feasibility of YP Face IT, an innovative online psychological intervention using social skills training and cognitive behavioural therapy, to Dutch adolescents. Adolescents aged 12-17 with a visible difference and access to an internet-enabled computer or tablet participated. They completed YP Face IT (eight sessions) and questionnaires were administered pre- and post-intervention. After completing YP Face IT, participants were interviewed to assess the acceptability and feasibility of YP Face IT and study procedures. Overall, 15 adolescents consented to participation, one person dropped out after one session. Most adolescents appreciated the intervention and all would recommend it to other adolescents experiencing appearance-related distress. Everyone reported learning experiences after following the sessions. Some struggled with motivation, but reminders by the website and research team were helpful. The Dutch YP Face IT intervention may be acceptable and the current study design is feasible to use. An RCT should be conducted to assess the effectiveness of the intervention.

Feeding and swallowing outcomes following mandibular distraction osteogenesis: an analysis of 22 non-isolated paediatric cases.

Patients with mandibular hypoplasia and upper airway obstruction are at an increased risk of feeding and swallowing difficulties. Little has been described regarding these outcomes following mandibular distraction. The aim of this study was to evaluate the effect of mandibular distraction on feeding and swallowing function. A retrospective study was performed on 22 patients with non-isolated mandibular hypoplasia and severe upper airway obstruction treated with mandibular distraction. Median age at first mandibular distraction was 3.1 years (interquartile range 2.3-6.0 years) and the median follow-up time was 3.5 years (interquartile range 2.0-9.4 years). Prior to mandibular distraction, feeding difficulties were present in 18 patients. Swallowing difficulties were present in 20 patients, all of whom had problems in the oral phase of swallowing, while 11 patients had additional problems in the pharyngeal phase. Following mandibular distraction, at the time of follow-up, feeding difficulties persisted in 13 patients. Swallowing difficulties in the oral phase remained present in all 20 patients, while pharyngeal phase problems persisted in seven patients. In conclusion, feeding and swallowing difficulties are highly prevalent in non-isolated patients and often persist following mandibular distraction. Moreover, these can be the reason that decannulation cannot be accomplished. Hence, awareness and close follow-up by a specialized speech therapist is of paramount importance.

Targeted ultrasound examination and DNA testing for Noonan syndrome, in fetuses with increased nuchal translucency and normal karyotype.

OBJECTIVE: To define sonographic criteria that may improve the prenatal diagnosis of Noonan syndrome by targeted DNA testing. METHODS: We searched our Fetal Medicine Unit records for all cases with a final diagnosis of Noonan syndrome. A literature review was undertaken to identify the sonographic features of Noonan syndrome fetuses. Information was pooled to define the most common features. RESULTS: In our database, we identified three cases of Noonan syndrome. The diagnosis was suspected prenatally in two of them. Thirty-nine cases were identified in the literature. In the presented cases we show that suspicion of Noonan syndrome should arise when, after an increased nuchal translucency, ultrasound investigation in the second trimester shows a persistant nuchal fold (NF) or cystic hygroma in combination with at least one of the following features: hydrops fetalis, pleural effusion, cardiac anomalies, polyhydramnios or specific facial abnormalities. CONCLUSION: Prenatal ultrasound findings in Noonan syndrome can be subtle and aspecific, but when specific characteristics are present additional targeted DNA analysis is indicated.

Audit of 10 years of referrals for fetal echocardiography.

OBJECTIVES: To evaluate trends over time, indications, diagnoses, noncardiac defects and outcome of fetuses referred for tertiary level echocardiography. METHODS: Retrospective study of fetal echocardiograms performed between April 1999 and 2009. RESULTS: Of the 623 fetuses included, 301 (48%) had cardiac pathology. Congenital heart defects (CHDs) were found in 243/301 (81%), mostly in the severe spectrum. Of the fetuses with CHDs, 26% (63/243) had chromosomal anomalies. The chromosomally normal fetuses with CHDs had a mortality rate of 43% (77/180) and 23% (41/180) had extra-cardiac anomalies. The termination of pregnancy (TOP) rate for all cardiac pathology was 24.9% (75/301) and for CHDs 29.6% (72/243). The TOP rates for CHDs diagnosed before 19 and 24 weeks gestation were 61% (28/46) and 44% (68/155), respectively. An increase in referrals followed the introduction of a national screening program, (nuchal translucency (NT) and routine structural ultrasound screening). The main referral indication was an increased NT (>95th percentile; 32% of cases). CHDs were found in 81/239 (34%) fetuses with an increased NT. CONCLUSIONS: Referral indications for fetal echocardiography were appropriate (almost 50% had cardiac pathology). The mortality was high. Fetal outcome and TOP decisions correlated with CHD severity and presence of noncardiac defects. An increased NT is a strong marker for CHDs.

Characteristics and outcome and the omphalocele circumference/abdominal circumference ratio in prenatally diagnosed fetal omphalocele.

OBJECTIVE: To evaluate the outcome of fetuses with prenatally diagnosed omphalocele and to investigate the predictive value of the omphalocele circumference/abdominal circumference (OC/AC) ratio - a measure for the relative size of the omphalocele. MATERIALS AND METHODS: This study includes all fetuses prenatally diagnosed with omphalocele at our centre between 1995 and 2007. Medical records and footage of ultrasound examinations were reviewed. Omphalocele was classified in four groups: isolated, chromosomal, syndromic, and multiple anomalies. RESULTS: Eighty-eight cases were identified: 21 (24%) were isolated and 67 had additional structural anomalies. Of the 44 fetuses (50%) with chromosomal anomalies, 2 had omphalocele as a solitary finding. Fifty-three pregnancies (60%) were terminated because of the size of the lesion or associated structural or chromosomal anomalies. Twenty-one cases resulted in a live birth, of which 17 were vaginal deliveries (81%, all uncomplicated) including 3 cases of giant omphalocele (≥5 cm). The OC/AC ratio was found predictive for herniation of the liver, respiratory insufficiency and type of surgical reconstruction. Currently, 12/88 fetuses (14%) are alive and well, including 2 infants with multiple anomalies. CONCLUSION: Identification of omphalocele should arouse suspicion of genetic abnormalities, even in cases that appear isolated. The OC/AC ratio may influence counselling regarding the postnatal course.

Functional outcomes in patients with facial dysostosis and severe upper airway obstruction.

An increased risk of upper airway obstruction (UAO) is seen in up to 95% of patients with facial dysostosis. Secondary to respiratory problems are feeding difficulties and increased nutritional requirements. Little has been described regarding these outcomes in this patient population. Hence, a retrospective cohort study was performed to gather data on functional outcomes. Eighteen patients with facial dysostosis and severe UAO were included. The median follow-up time was 3.42 years. A tracheostomy tube was placed in 13 patients, of whom 10 subsequently underwent mandibular distraction. Three of the five patients without a tracheostomy underwent mandibular distraction as the primary surgical treatment; the remaining two patients were treated conservatively with oxygen supplementation. At presentation, 13 patients had feeding difficulties. Overall malnutrition was present in 16 patients during follow-up. At the end of follow-up, severe UAO was present in 12 patients, feeding difficulties in seven patients, and malnutrition in four patients, while two patients died. In conclusion, patients with facial dysostosis have a high prevalence of severe UAO, feeding difficulties, and malnutrition. Importantly, mandibular distraction has limited success in treating severe UAO in these patients. Close follow-up by a specialized craniofacial team is of paramount importance to manage the long-term consequences.

Cervical Spinal Cord Compression and Sleep-Disordered Breathing in Syndromic Craniosynostosis.

BACKGROUND AND PURPOSE: Cerebellar tonsillar herniation arises frequently in syndromic craniosynostosis and causes central and obstructive apneas in other diseases through spinal cord compression. The purposes of this study were the following: 1) to determine the prevalence of cervical spinal cord compression in syndromic craniosynostosis, and 2) to evaluate its connection with sleep-disordered breathing. MATERIALS AND METHODS: This was a cross-sectional study including patients with syndromic craniosynostosis who underwent MR imaging and polysomnography. Measures encompassed the compression ratio at the level of the odontoid process and foramen magnum and the cervicomedullary angle. MR imaging studies of controls were included. Linear mixed models were developed to compare patients with syndromic craniosynostosis with controls and to evaluate the association between obstructive and central sleep apneas and MR imaging parameters. RESULTS: One hundred twenty-two MR imaging scans and polysomnographies in 89 patients were paired; 131 MR imaging scans in controls were included. The mean age at polysomnography was 5.7 years (range, 0.02-18.9 years). The compression ratio at the level of the odontoid process was comparable with that in controls; the compression ratio at the level of the foramen magnum was significantly higher in patients with Crouzon syndrome (+27.1, P < .001). The cervicomedullary angle was significantly smaller in Apert, Crouzon, and Saethre-Chotzen syndromes (-4.4°, P = .01; -10.2°, P < .001; -5.2°, P = .049). The compression ratios at the level of the odontoid process and the foramen magnum, the cervicomedullary angle, and age were not associated with obstructive apneas (P > .05). Only age was associated with central apneas (P = .02). CONCLUSIONS: The prevalence of cervical spinal cord compression in syndromic craniosynostosis is low and is not correlated to sleep disturbances. However, considering the high prevalence of obstructive sleep apnea in syndromic craniosynostosis and the low prevalence of compression and central sleep apnea in our study, we would, nevertheless, recommend a polysomnography in case of compression on MR imaging studies.