BackgroundVariants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear.MethodsWe examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.ResultsPathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.ConclusionsPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.
Children with Down syndrome (DS) are at a 20‐fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non‐DS‐ALL), those with DS and ALL (DS‐ALL) harbor uncommon genetic alterations, suggesting DS‐ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS‐ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS‐ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non‐DS‐ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome‐like subtype, a high‐risk B‐cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS‐ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS‐ALL, but not non‐DS‐ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B‐cell precursors might be associated with increased incidence of B‐cell precursor ALL in DS patients.
Background: Niemann-Pick type C (NPC) is a lysosomal lipid storage disease with mutation of NPC1/NPC2 genes, which transport lipids in the endosome and lysosome, and various neurological symptoms. NPC patients also develop hepatosplenomegaly or liver disorder in the neonatal period, and 10% suffer severe liver failure. Neonatal hemochromatosis (NH) is a liver disorder characterized by hepatic and extrahepatic siderosis. Although the etiology of NH is unclear, recent reports suggest that the gestational alloimmune mechanism is the cause of NH. Herein, we report a Japanese NPC patient initially diagnosed as NH.Case report: A 5-day-old boy was transferred to our hospital with severe cholestatic liver failure. Congenital infections and metabolic screening were negative, and NH was suspected. However intra and extrahepatic siderosis were not found. As his liver deteriorated rapidly, liver transplantation was performed at 19 days old. The explanted liver showed cirrhosis, and strong C5b-9 complex staining of hepatocytes, so NH was diagnosed. From the age of one and a half years, he developed regression, vertical supranuclear gaze palsy and cataplexy. Fibroblast filipin staining was strong, blood oxysterol was high, and there were compound heterozygous mutations in NPC1,p.[(F288L)];[(K1206N)]. The patient was then diagnosed as NPC and started on miglustat.Conclusion: Neonatal liver failure was initially diagnosed as NH. Later, the patient developed various neurological symptoms characteristic of NPC. Neurological follow-up of children who develop NH is required.
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