Sudden death in epilepsy and ectopic neurohypophysis in Joubert syndrome 23 diagnosed using SNVs/indels and structural variants pipelines on WGS data: a case report.

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.

Nutritional rickets in Norway: a nationwide register-based cohort study.

OBJECTIVES: Poor vitamin D status has been reported to be highly prevalent in many non-western immigrant groups living in Norway and other western countries. However, data on rickets are scarce, and the aim of the current study was to identify new cases of nutritional rickets in Norway in the period 2008-2012 among children under the age of 5 years. DESIGN: Register-based cohort study. SETTING: The Norwegian population from 2008 to 2012. PARTICIPANTS: Children with nutritional rickets under the age of 5 years. MAIN OUTCOME MEASURE: Nutritional rickets. Patients with ICD10 (International Statistical Classification of Diseases and Related Health Problems, 10th revision) diagnosis code E55.0 (active rickets) treated at all Norwegian hospitals were identified in the Norwegian Patient Registry. We were able to review 85% of the medical records for diagnosis confirmation. In addition, we identified patients with the diagnoses E55.9, E64.3 and E83.3 to identify individuals with rickets who had been given other diagnoses. RESULTS: Nutritional rickets was confirmed in 39 children aged 0-4 years with the diagnosis of E55.0. In addition, three patients with the diagnosis of unspecified vitamin D deficiency (E55.9) were classified as having nutritional rickets, giving a total of 42 patients. Mean age at diagnosis was 1.40 years (range 0.1-3.5 years), and 93% had a non-western immigrant background. The incidence rate of rickets was estimated to be 0.3 per 10 000 person-years in the total Norwegian child population under the age of 5 years and 3.1 per 10 000 person-years in those with an immigrant background from Asia or Africa. CONCLUSION: The number of children with nutritional rickets in Norway remained low in the period 2008-2012. Nearly all children had a non-western immigrant background.