We examined neuropathologically and immunohistochemically the respiratory centers in the brainstem of two patients with Joubert syndrome (JS), three patients with congenital central hypoventilation syndrome (CCHS) and a patient with apneustic breathing (prolonged inspiratory pause) due to unknown etiology. Immunoreactivity (IR) of tryptophan hydroxylase (TPH) was decreased in the dorsal raphe nuclei of two patients with JS compared with age-matched controls, as well as in two patients with Dandy-Walker malformation. The two JS patients showed vermian defect and elongated cerebellar peduncles, and peculiar vascularities in the midline of the whole brainstem were also noted in one of these patients. These findings, as a whole, confirm that the midline structures of brainstem are disordered both structurally and functionally in JS, conceivably resulting in respiratory patterns and psychomotor deficits. IR of serotonin 1A receptor showed no significant changes in the medulla oblongata of these patients, however. In the parabrachial complex, IR of substance P was increased in two patients with CCHS, and one with apneustic breathing. IR of tyrosine hydroxylase was also increased in the latter. The brainstem of these patients showed reactive astrogliosis. These findings suggest preceding hypoxic episodes as well as an increased activity in the parabrachial complex which plays an important role in conducting the driving force to the medullary respiratory neurons from ascending sensory pathways.
The TWIST family is a group of highly conserved basic helix–loop–helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre–Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon‐macrostomia syndrome, respectively. Sweeney–Cox syndrome, Barber–Say syndrome, and ablepharon‐macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth. Existence of phenotypic overlap between Saethre–Chotzen syndrome and Sweeney–Cox syndrome remains unknown. Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C>G p.Glu117Asp. The pathogenicity of this variant was supported by in silico and in vivo evidence. Our review showed that Sweeney–Cox syndrome appears to share many characteristics with Barber–Say syndrome and ablepharon‐macrostomia syndrome except for craniosynostosis, which is a cardinal feature of Saethre–Chotzen syndrome. An amino acid substitution from Glu117 to Asp, both of which are the sole members of negatively charged amino acids, resulted in a prototypic Sweeney–Cox syndrome phenotype. This suggests that any amino acid substitutions at Glu117 would likely lead to the Sweeney–Cox syndrome phenotype or lethality. The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon.
Purpose The optimal timing of surgery for congenital diaphragmatic hernia (CDH) is controversial. We aimed to validate our protocol for the timing of CDH repair using the quantified patent ductus arteriosus (PDA) flow pattern. Methods This retrospective comparative study analyzed patients with a prenatal diagnosis of isolated CDH between 2007 and 2020. We defined the "LR ratio" as the percentage of velocity-time integral (VTI) of the left-to-right flow of PDA against overall VTI on echocardiography. Since 2010, we followed the decision criterion of performing surgery when LR ratio of > 50% has been achieved in the patients (protocol group). The protocol group (2010-2020) was compared with the historical control group (2007)(2008)(2009). Results The average age at surgery was 104.1 ± 175.9 and 37.3 ± 30.6 h in the control and protocol groups, respectively (p = 0.11). Survival rate (88.9% vs. 95.0%, p = 0.53) and the rate of worsening of pulmonary hypertension within 24 h after surgery (22.2% vs. 10.0%, p = 0.57) were not different between the groups. The protocol group had a significantly shorter duration of tracheal intubation (26.9 ± 21.1 vs. 13.3 ± 9.5 days, p = 0.03). Conclusion Our decision criterion might have the advantage of facilitating early and safe surgery for patients with CDH.
Background: Infant flow biphasic nasal continuous positive airway pressure (Bi-NCPAP) and regular NCPAP (Re-NCPAP) are equally useful with respect to the rate of successful weaning from mechanical ventilation. However, it remains unclear whether Bi-NCPAP or Re-NCPAP is more effective for reducing apnea of prematurity (AOP).
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