ARTICLE Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications

PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications

Genotype-phenotype correlation at codon 1740 ofSETD2

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluati

Oesophageal elongation with traction sutures (FOKER procedure) in a newborn baby with long-gap oesophageal atresia (LGEA): Maybe too early, maybe too dangerous?

In children with long gap oesophageal atresia (LGEA), the FOKER technique (oesophageal elongation with traction sutures) has been criticized for its high complication rate. We advocate analysing such problems to increase the safety in the future. The present case report will focus on timing. A female newborn (3000 g) with LGEA (gap of 5 cm) was delivered in an outward hospital. On day two of life, she received traction sutures on both pouches. By day five, all sutures had torn out, and a primary anastomosis was attempted. However, it leaked severely. Thus, on day ten, the oesophagus was approached from the neck converting the proximal end into a spit fistula and closing the distal end blindly. Furthermore, the gastro-oesophageal (GE-) junction was wrapped with a Teflon sling. When the baby arrived in our institution, she suffered from cavernous oesophageal masses extending from the thoracic inlet down to the diaphragm and fistulas draining them into the neck as well as into the right lung. Moreover, the Teflon sling had dislodged allowing for GE-reflux. In several stages, the oesophageal remnants were resected without any complications. Finally, Prof. Alaa Hamza performed a colonic interposition, which is working well today. In conclusion, the present case aims to caution paediatric surgeons to apply traction sutures for oesophageal elongation in newborns with LGEA

Bunk-Bed-Related Fractures in Children: Are We Aware of the Risks?

Background and Objectives: Falls from heights are a common mechanism of trauma in children. However, data on bunk-bed-related (BBR) fractures are scarce. We aimed to assess types of fractures and age groups most at risk for BBR fractures. Material and Methods: We analyzed medical records and imaging procedures of patients aged Results: A total of 162 patients (median age 5 years, range 0–15; 59.9% male) was included. Fractures were recorded in 80 (49.4%) and contusions and abrasions in 49 (30.2%) cases. BBR fractures were recorded in 44.8% of children below the age of 3, in 50.8% aged 3–5, in 58.5% aged 6–9 and in 28.6% ≥ 10 years. Forearm fractures were most common (n = 34, 42.5%), followed by fractures of the clavicle (n = 13, 16.3%), humerus (n = 10, 12.5%), foot (n = 8, 10.0%), hand (n = 5, 6.3%), lower leg (n = 5, 6.3%) and skull (n = 5, 6.3%). Surgery was required in 12 (15.0%) cases, including closed reduction (n = 7) and closed reduction with internal fixation (n = 5). Overall, 21 (26.3%) patients were hospitalized with a mean length of stay of 2 ± 1.6 days. Conclusions: Caregivers should be aware that bunk beds cause a significant amount of severe trauma in children and adolescents, especially in those younger than 10 years of age. Caregivers would benefit from receiving information about these risks and evidence-based strategies to prevent BBR fractures

Bunk-Bed-Related Fractures in Children: Are We Aware of the Risks?

Background and Objectives: Falls from heights are a common mechanism of trauma in children. However, data on bunk-bed-related (BBR) fractures are scarce. We aimed to assess types of fractures and age groups most at risk for BBR fractures. Material and Methods: We analyzed medical records and imaging procedures of patients aged <18 years who sustained a bunk bed injury and were treated at our department between January 2014 and December 2021. Demographic data, including age groups, mechanisms, types and anatomical regions of fractures, were assessed. Results: A total of 162 patients (median age 5 years, range 0–15; 59.9% male) was included. Fractures were recorded in 80 (49.4%) and contusions and abrasions in 49 (30.2%) cases. BBR fractures were recorded in 44.8% of children below the age of 3, in 50.8% aged 3–5, in 58.5% aged 6–9 and in 28.6% ≥ 10 years. Forearm fractures were most common (n = 34, 42.5%), followed by fractures of the clavicle (n = 13, 16.3%), humerus (n = 10, 12.5%), foot (n = 8, 10.0%), hand (n = 5, 6.3%), lower leg (n = 5, 6.3%) and skull (n = 5, 6.3%). Surgery was required in 12 (15.0%) cases, including closed reduction (n = 7) and closed reduction with internal fixation (n = 5). Overall, 21 (26.3%) patients were hospitalized with a mean length of stay of 2 ± 1.6 days. Conclusions: Caregivers should be aware that bunk beds cause a significant amount of severe trauma in children and adolescents, especially in those younger than 10 years of age. Caregivers would benefit from receiving information about these risks and evidence-based strategies to prevent BBR fractures