Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis.

An accurate diagnosis of syndromic craniosynostosis (CS) is important for personalized treatment, surveillance, and genetic counselling. We describe detailed clinical criteria for syndromic CS and the distribution of genetic diagnoses within the cohort. The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve individuals with syndromic CS born between 1 January 2002 and 30 June 2019. All individuals were assessed by a clinical geneticist and classified using defined clinical criteria. A stepwise approach consisting of single-gene analysis, comparative genomic hybridization (aCGH), and exome-based high-throughput sequencing, first filtering for 72 genes associated with syndromic CS, followed by an extended trio-based panel of 1570 genes were offered to all syndromic CS cases. A total of 381 individuals were registered with CS, of whom 104 (27%) were clinically classified as syndromic CS. Using the single-gene analysis, aCGH, and custom-designed panel, a genetic diagnosis was confirmed in 73% of the individuals (n = 94). The diagnostic yield increased to 84% after adding the results from the extended trio-based panel. Common causes of syndromic CS were found in 53 individuals (56%), whereas 26 (28%) had other genetic syndromes, including 17 individuals with syndromes not commonly associated with CS. Only 15 individuals (16%) had negative genetic analyses. Using the defined combination of clinical criteria, we detected among the highest numbers of syndromic CS cases reported, confirmed by a high genetic diagnostic yield of 84%. The observed genetic heterogeneity encourages a broad genetic approach in diagnosing syndromic CS.

Epidemiology of craniosynostosis in Norway.

OBJECTIVE: The authors present population-based epidemiological data for craniosynostosis regarding incidence, age at diagnosis, sex differences, and frequency of syndromic and familial cases. METHODS: The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve data on all individuals with craniosynostosis treated between 2003 and 2017. The cohort was divided into three 5-year groups based on year of birth: 2003-2007, 2008-2012, and 2013-2017. RESULTS: The authors identified 386 individuals with craniosynostosis. Of these, 328 (85%) consented to be registered with further information. The incidence increased significantly during the study period and was 5.5 per 10,000 live births (1/1800) in the last 5-year period. The increase was seen almost exclusively in the nonsyndromic group. Syndromic craniosynostosis accounted for 27% of the cases, and the incidence remained stable throughout the three 5-year periods. Both syndromic and nonsyndromic craniosynostosis were highly suture specific. There was a male preponderance (male/female ratio 2:1), and males accounted for 75% of the individuals with midline synostosis. Overall, 9.5% were index individuals in families with more than one affected member; of these, 73% were nonsyndromic cases. CONCLUSIONS: The incidence of craniosynostosis increased during the study period, and the observed incidence is among the highest reported. The authors attribute this to increasing awareness among healthcare professionals. The number of syndromic cases was high, likely due to a broader definition compared to the majority of earlier reports. The study revealed a high number of familial cases in both syndromic and nonsyndromic craniosynostosis, thus highlighting the importance of genetics as an underlying cause of craniosynostosis.

Epidemiology of Benign External Hydrocephalus in Norway-A Population-Based Study.

BACKGROUND: Benign external hydrocephalus is defined as a rapidly increasing head circumference (occipitofrontal circumference) with characteristic radiological findings of increased subarachnoid cerebrospinal fluid spaces on neuroimaging. The incidence of benign external hydrocephalus has not been previously reported, and there is no available information on the ratio of benign external hydrocephalus in the population of hydrocephalic children. METHODS: This study is retrospective and population-based study, geographically covering two health regions in the southern half of Norway with a total mean population of 3.34 million in the ten-year study period, constituting approximately 75% of the Norwegian population. Children with a head circumference crossing two percentiles, or greater than the 97.5th percentile, and with typical imaging findings of enlarged frontal subarachnoid spaces with or without enlarged ventricles were included. Children were excluded if they had a history of head trauma, intracranial hemorrhage, central nervous system infection, other known causes of hydrocephalus, or were born preterm defined as birth before 37 weeks of gestation. RESULTS: A total of 176 children fitting the criteria were identified, giving an incidence of 0.4 per 1000 live births. One hundred fifty-two (86.4%) of the patients were male, and mean age at referral was 7.3 months. Increasing head circumference was the main reason for referral in 158 (89.8%) patients and the only finding in 60 (34.1%) patients. Thirty-seven (21%) children had normal ventricles on imaging; the remainder had increased ventricular size. The incidence of pediatric hydrocephalus in Norway is reported to be 0.75 per 1000 live births, thus benign external hydrocephalus accounts for approximately 50% of hydrocephalic conditions in this population. CONCLUSIONS: The incidence of benign external hydrocephalus was found to be 0.4 per 1000 live births in this population.

Neurocognitive and psychosocial function in children with benign external hydrocephalus (BEH)-a long-term follow-up study.

INTRODUCTION: Long-term impact of benign external hydrocephalus (BEH) on cognition is largely unknown, and indication for neurosurgical CSF diversion procedure is debated. This study reports neuropsychological and psychosocial function in operated and non-operated BEH children. METHODS: Eighty-six children (76 males) between 8 and 18 years (mean 13.9) diagnosed with BEH before 12 months were included, of whom 30.2 % were operated. Participants completed neuropsychological tests and questionnaires covering quality of life (PedsQL) and executive function (BRIEF). RESULTS: Both operated and non-operated BEH children performed significantly below normative means on several neuropsychological tests. The children scored themselves higher than the norm average on PedsQL; however, the parents reported life quality comparable to other children. Operated children performed poorer compared with non-operated children on tests of psychomotor speed, attention span, executive function, motor speed and coordination, and on the BRIEF subscale Monitoring. Operated children, but not their parents, reported more problems on PedsQL subscale School than non-operated children. DISCUSSION: Children with BEH display long-term subtle neurocognitive difficulties. Non-operated children performed significantly better on some neuropsychological measures and reported less psychosocial problems. This difference may be caused by a selection bias: neurosurgical intervention was more likely in children with clinically more pronounced symptoms.

Spontaneous knot; a rare cause of ventriculoperitoneal shunt blockage.

A 14-year old X linked congenital hydrocephalus presented with unexplained headaches and vomiting. He had external ventricular drain and intracranial pressure monitoring (ICP). Subsequently, he underwent exploration and removal of previously inserted ventriculoperitoneal (VP) shunts. On retrieval of peritoneal catheters a double knot was noted between his two distal catheters. This case illustrates a rare cause of ventriculoperitoneal shunt malfunction.