Heterozygous pathogenic variants involving CBFB cause a new skeletal disorder resembling cleidocranial dysplasia.

BACKGROUND: Cleidocranial dysplasia (CCD) is a rare skeletal dysplasia with significant clinical variability. Patients with CCD typically present with delayed closure of fontanels and cranial sutures, dental anomalies, clavicular hypoplasia or aplasia and short stature. Runt-related transcription factor 2 (RUNX2) is currently the only known disease-causing gene for CCD, but several studies have suggested locus heterogeneity. METHODS: The cohort consists of eight subjects from five unrelated families partially identified through GeneMatcher. Exome or genome sequencing was applied and in two subjects the effect of the variant was investigated at RNA level. RESULTS: In each subject a heterozygous pathogenic variant in CBFB was detected, whereas no genomic alteration involving RUNX2 was found. Three CBFB variants (one splice site alteration, one nonsense variant, one 2 bp duplication) were shown to result in a premature stop codon. A large intragenic deletion was found to delete exon 4, without affecting CBFB expression. The effect of a second splice site variant could not be determined but most likely results in a shortened or absent protein. Affected individuals showed similarities with RUNX2-related CCD, including dental and clavicular abnormalities. Normal stature and neurocognitive problems were however distinguishing features. CBFB encodes the core-binding factor ß subunit, which can interact with all RUNX proteins (RUNX1, RUNX2, RUNX3) to form heterodimeric transcription factors. This may explain the phenotypic differences between CBFB-related and RUNX2-related CCD. CONCLUSION: We confirm the previously suggested locus heterogeneity for CCD by identifying five pathogenic variants in CBFB in a cohort of eight individuals with clinical and radiographic features reminiscent of CCD.

Pelvic floor awareness and the positive effect of verbal instructions in 958 women early postdelivery.

INTRODUCTION AND HYPOTHESIS: It is uncertain how reliable a personal belief is about the ability to do pelvic floor muscle (PFM) contractions early postdelivery and how instructional feedback affects pelvic floor muscle contraction (PFMC) performance. We hypothesize that many women do not have a reliable idea about PFMC and that instructional feedback can help improve their control. METHODS: Prospective observational study in 958 women (median 30 years) early postdelivery PFMC was evaluated with visual observation: an inward movement of the perineum was accepted as sign of good contraction. The women who could not show PFMC three consecutive times got verbal instructions, and re-evaluation was afterward. RESULTS: In 500 women, no inward movement of the perineum was observed: 275 women (29%) showed no movement at all, and 225 women (24%) showed some movement but no inward displacement. In 33.4%, the personal conviction to be able or not to perform PFMC proved false. After verbal instructions, 74% improved their PFMC. CONCLUSIONS: The belief of doing correct PFM contraction was false in at least one of five postpartum women. Verbal instructions have a positive effect on performing PFMC in 73.6% of women.

Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations.

Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, joint limitations, diverse cardiovascular and airway manifestations, and increased fibrosis often following trauma or surgery. In contrast, adults with MS are underreported obscuring potential clinical variability. Here, we describe 24 adults with MS, including 17 diagnosed after the age of 18 years old, and we review the literature on adults with MS. Overall, our cohort shows a milder phenotype as well as lower mortality rates compared to what has been published in literature. Individuals with a codon 500 variant in SMAD4 present with a more pronounced neurodevelopmental and systemic phenotype. However, in contrast to the literature, we observe cardiovascular abnormalities in individuals with the p.(Arg496Cys) variant. In addition, we describe scoliosis as a new manifestation and we report fertility in two additional males with the p.(Arg496Cys). In conclusion, our study contributes novel insights into the clinical variability of MS and underscores the importance of variant-specific considerations, and we provide recommendations for the management of MS in adulthood.

The prevalence of hypercapnia during acute infection in children on chronic noninvasive ventilation: A retrospective study.

BACKGROUND/AIM: Children on chronic noninvasive ventilation are at risk for nonelective hospitalizations, mainly for acute infections. This study examined the prevalence of hypercapnia in children on chronic ventilatory support during an acute admission. METHODS: This retrospective study included children aged 0 to 18 years who regularly used bilevel positive airway pressure or continuous positive airway pressure at home, and who were diagnosed with an acute infection, and were hospitalized at the pediatrics department or pediatric intensive care unit. Capillary blood gas analysis and parameters of the built-in software of the home ventilator were recorded. RESULTS: Among the 43 cases included, hypercapnia was prevalent in 23% with a mean partial pressure of carbon dioxide of 51.7 ± 6.4 mm Hg. These children also had lower oxygen saturation levels. The respiratory rate 48 hours before admission was significantly higher in the hypercapnic group and the volume guarantee mode was less frequently used in the hypercapnic group. CONCLUSION: Approximately, a quarter of the cases of chronic home ventilation experience hypercapnia during an acute infection. Our data warrant a prospective study on the monitoring of respiratory rate in patients with chronic respiratory insufficiency as an indicator for hospitalizations with hypercapnia; we also recommend the use of volume guarantee mode of ventilation to prevent hypercapnia.