Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review.

Biallelic variants in the OTUD6B gene have been reported in the literature in association with an intellectual developmental disorder featuring dysmorphic facies, seizures, and distal limb abnormalities. Physical differences described for affected individuals suggest that the disorder may be clinically recognizable, but previous publications have reported an initial clinical suspicion for Kabuki syndrome (KS) in some affected individuals. Here, we report on three siblings with biallelic variants in OTUD6B co-segregating with neurodevelopmental delay, shared physical differences, and other clinical findings similar to those of previously reported individuals. However, clinical manifestations such as long palpebral fissures, prominent and cupped ears, developmental delay, growth deficiency, persistent fetal fingertip pads, vertebral anomaly, and seizures in the proband were initially suggestive of KS. In addition, previously unreported clinical manifestations such as delayed eruption of primary dentition, soft doughy skin with reduced sweating, and mirror movements present in our patients suggest an expansion of the phenotype, and we perform a literature review to update on current information related to OTUD6B and human gene-disease association.

Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants.

Patent ductus arteriosus (PDA) and coarctation of the aorta (CoA) are relatively common congenital heart defects. Pathogenic variants in PRDM6, which encodes a smooth-muscle-cell-specific transcription factor, have now been etiologically associated with non-syndromic PDA. We present three patients with PDA and CoA found to harbor PRDM6 variants, including a novel, likely-pathogenic variant.

Monoallelic loss-of-function BMP2 variants result in BMP2-related skeletal dysplasia spectrum.

PURPOSE: Bone morphogenic proteins (BMPs) regulate gene expression that is related to many critical developmental processes, including osteogenesis for which they are named. In addition, BMP2 is widely expressed in cells of mesenchymal origin, including bone, cartilage, skeletal and cardiac muscle, and adipose tissue. It also participates in neurodevelopment by inducing differentiation of neural stem cells. In humans, BMP2 variants result in a multiple congenital anomaly syndrome through a haploinsufficiency mechanism. We sought to expand the phenotypic spectrum and highlight phenotypes of patients harboring monoallelic missense variants in BMP2. METHODS: We used retrospective chart review to examine phenotypes from an international cohort of 18 individuals and compared these with published cases. Patient-derived missense variants were modeled in zebrafish to examine their effect on the ability of bmp2b to promote embryonic ventralization. RESULTS: The presented cases recapitulated existing descriptions of BMP2-related disorders, including craniofacial, cardiac, and skeletal anomalies and exhibit a wide phenotypic spectrum. We also identified patients with neural tube defects, structural brain anomalies, and endocrinopathies. Missense variants modeled in zebrafish resulted in loss of protein function. CONCLUSION: We use this expansion of reported phenotypes to suggest multidisciplinary medical monitoring and management of patients with BMP2-related skeletal dysplasia spectrum.

EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis.

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.

Expanding the phenotype of males with OFD1 pathogenic variants-a case report and literature review.

Pathogenic variants in the OFD1 gene have been classically associated with the Orofaciodigital syndrome type 1 in females, a condition previously considered to be X-linked dominant with male embryonic lethality. However, an increasing number of males with pathogenic OFD1 variants who survived beyond the neonatal period have now been reported in the literature. Although each new report has added to the ever-broadening spectrum of clinical findings seen in males, many questions about genotype-phenotype correlations and disease mechanism remain. Herein, we describe a 9-year-old male child with a novel hemizygous pathogenic OFD1 variant identified by exome sequencing and a unique combination of findings, not previously reported, including presence of both a hypothalamic hamartoma and the molar tooth sign. His clinical features overlap multiple ciliopathy phenotypes, blurring the boundaries of distinct ciliopathy gene-disease relationships. This case provides further evidence for the consideration of a broad OFD1-relateddisorder spectrum in affected males rather than multiple distinct phenotypes. Additionally, a review of previously published cases of the disorder in males support the inclusion of the OFD1 gene in the differential diagnosis and work up for all individuals who present with primary ciliopathy-type features, regardless of their gender. We also highlight current information about OFD1 variant types and pathogenesis and explore how these could mechanistically drive some of the observed phenotypic differences.

A randomized controlled trial of vapocoolant for pediatric immunization distress relief.

OBJECTIVES: The purpose of this study was to evaluate the effectiveness of vapocoolant for preschoolers' immunization injection pain relief. METHODS: Fifty-seven 4 to 6-year-old children were randomized into vapocoolant alone or typical care conditions. Pain was measured at the baseline and at injection via self-report, caregiver report, nurse report, and by an observational scale. RESULTS: Self-report of pain suggested that children in the vapocoolant alone condition demonstrated stronger increases in pain from baseline to injection than children in the typical care condition. All other measures showed significant increases in pain from baseline to injection, but no other measures indicated treatment effects. DISCUSSION: This study revealed that vapocoolant is not an effective pain management intervention for children's intramuscular injections.

Randomized clinical trial of distraction for infant immunization pain.

Distraction has been shown to be an effective technique for managing pain in children; however, few investigations have examined the utility of this technique with infants. The goal of the current study was to investigate the effectiveness of movie distraction in reducing infants' immunization distress. Participants were 136 infants (range=1-21 months; M=7.6 months, SD=5.0 months) and their parents, all of whom were recruited when presenting for routine vaccinations. The parent-child dyads were randomly assigned to either a Distraction or Typical Care control condition. Infant and adult behaviors were assessed using a visual analog scale and a behavioral observation rating scale. Results indicated parents in the Distraction group engaged in higher rates of distraction than those in the Typical Care group, whereas there was no difference in the behavior of nurses in the Distraction and Typical Care groups. In addition, infants in the Distraction group displayed fewer distress behaviors than infants in the Typical Care group both prior to and during recovery from the injection. Findings suggest that a simple and practical distraction intervention can provide some distress relief to infants during routine injections.