Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.

Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.

A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform.

Import of peroxisomal matrix proteins, crucial for peroxisome biogenesis, is mediated by the cytosolic receptors PEX5 and PEX7 that recognize proteins carrying peroxisomal targeting signals 1 or 2 (PTS1 or PTS2), respectively. Mutations in PEX5 or 12 other PEX genes cause peroxisome biogenesis disorders, collectively named the Zellweger spectrum disorders (ZSDs), whereas mutations in PEX7 cause rhizomelic chondrodysplasia punctata type 1 (RCDP1). Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis. Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in PEX5. In four patients with RCDP from two independent families, we identified a homozygous frame shift mutation c.722dupA (p.Val242Glyfs(∗)33) in PEX5 (GenBank: NM_001131023.1). PEX5 encodes two isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation, located in the PEX5L-specific exon 9, results in loss of PEX5L only. Both PEX5 isoforms recognize PTS1-tagged proteins, but PEX5L is also a co-receptor for PTS2-tagged proteins. Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of PTS1-tagged proteins. Similarly to mutations in PEX7, loss of PEX5L results in deficient import of PTS2-tagged proteins only, thus causing RCDP instead of ZSD. We demonstrate that PEX5L expression restores the import of PTS2-tagged proteins in patient fibroblasts. Due to the biochemical overlap between RCDP1 and RCDP5, sequencing of PEX7 and exon 9 in PEX5 should be performed in patients with a selective defect in the import of PTS2-tagged proteins.

PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.

Human phosphoglucomutase 3 (PGM3) catalyzes the conversion of N-acetyl-glucosamine (GlcNAc)-6-phosphate into GlcNAc-1-phosphate during the synthesis of uridine diphosphate (UDP)-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways. We identified three unrelated children with recurrent infections, congenital leukopenia including neutropenia, B and T cell lymphopenia, and progression to bone marrow failure. Whole-exome sequencing demonstrated deleterious mutations in PGM3 in all three subjects, delineating their disease to be due to an unsuspected congenital disorder of glycosylation (CDG). Functional studies of the disease-associated PGM3 variants in E. coli cells demonstrated reduced PGM3 activity for all mutants tested. Two of the three children had skeletal anomalies resembling Desbuquois dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability. However, these additional features were absent in the third child, showing the clinical variability of the disease. Two children received hematopoietic stem cell transplantation of cord blood and bone marrow from matched related donors; both had successful engraftment and correction of neutropenia and lymphopenia. We define PGM3-CDG as a treatable immunodeficiency, document the power of whole-exome sequencing in gene discoveries for rare disorders, and illustrate the utility of genomic analyses in studying combined and variable phenotypes.

Correction of postpneumonectomy syndrome in infants with saline-filled expandable prosthesis.

We report two infants who underwent right pneumonectomy in infancy and developed postpneumonectomy syndrome with obstruction of the left main bronchus causing severe airway obstruction in one patient and gastrointestinal reflux due to a displaced and grossly dilated oesophagus in the other patient. Both patients were operated with implantation of an expandable breast prosthesis.

Feasibility of long-term continuous EEG monitoring during the first days of life in preterm infants: an automated quantification of the EEG activity.

Long-term EEG monitoring (LTM) with several electrodes could be a useful tool for surveillance of the brain during the first critical days of life. This study aimed to assess the feasibility of multichannel LTM for automated analysis of EEG activity from d 1 to 3 using eight electrodes. Premature infants (GA <31 wk; n = 48) were continuously monitored for 3 d. EEG monitoring for a total of 3257 h was successfully performed. Total absolute band power (tABP) was calculated per second. Artifacts were removed visually or by an algorithm removing the highest 5, 10, 15, and 20% tABPs. NS difference was found between the trends of visually edited and 5% mathematically trimmed data. Two groups were compared (24 ≤ GA < 28 wk and 28 ≤ GA < 31 wk) using the median of tABP for all frequency bands per day. The results showed that tABP differed between groups. The changes of tABP d 1-3 were equal in both groups. Automatically assessed LTM confirms that the EEG activity depends on GA. However, it reveals that the early changes (d 1-3) are independent of GA. The study demonstrates the feasibility of multichannel LTM and the possibility of developing automated EEG analyses.

Phenotypic variation in Melnick-Needles syndrome is not reflected in X inactivation patterns from blood or buccal smear.

Melnick-Needles syndrome is a rare putative X-linked dominant bone dysplasia. The patients have short stature, characteristic facial features, and a normal intelligence. The skeletal dysplasia includes S-shaped curvature of tubular bones and sclerosis of the base of the skull. The phenotype of affected individuals varies, even within families. This could be related to X chromosome inactivation. We report here on a very mildly affected mother and her two severely affected daughters with characteristic features of Melnick-Needles syndrome. In addition, the two daughters had very similar pigmented nevi on their back. X chromosome inactivation analysis of blood DNA revealed a skewed X inactivation pattern in all three affected females, with the normal X chromosome as the predominating active X chromosome. The X inactivation pattern was similar in buccal smear and blood DNA in the mother and one of the daughters, whereas the other daughter had a skewed pattern in blood only. X chromosome inactivation in blood and buccal smear DNA therefore does not explain the phenotypic variation in this family. The skewed X chromosome inactivation is in agreement with X-linked inheritance of Melnick-Needles syndrome and suggests a critical role of the Melnick-Needles gene in hematopoietic cell proliferation. Clinical evidence indicates that Melnick-Needles syndrome is allelic to the otopalatodigital syndromes, which have been assigned to Xq26-28. Haplotype analysis of the X chromosomes in this family was in agreement with the localization of the gene for Melnick-Needles syndrome to Xq25-qtel.