Further description of two individuals with de novo p.(Glu127Lys) missense variant in the ASCL1 gene.

Achaete-Scute Family basic-helix-loop-helix (bHLH) Transcription Factor 1 (ASCL1) is a proneural transcription factor involved in neuron development in the central and peripheral nervous system. While initially suspected to contribute to congenital central hypoventilation syndrome-1 (CCHS) with or without Hirschsprung disease (HSCR) in three individuals, its implication was ruled out by the presence, in one of the individuals, of a Paired-like homeobox 2B (PHOX2B) heterozygous polyalanine expansion variant, known to cause CCHS. We report two additional unrelated individuals sharing the same sporadic ASCL1 p.(Glu127Lys) missense variant in the bHLH domain and a common phenotype with short-segment HSCR, signs of dysautonomia, and developmental delay. One has also mild CCHS without polyalanine expansion in PHOX2B, compatible with the diagnosis of Haddad syndrome. Furthermore, missense variants with homologous position in the same bHLH domain in other genes are known to cause human diseases. The description of additional individuals carrying the same variant and similar phenotype, as well as targeted functional studies, would be interesting to further evaluate the role of ASCL1 in neurocristopathies.

De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes.

KCNMA1 encodes the large-conductance Ca2+- and voltage-activated K+ (BK) potassium channel α-subunit, and pathogenic gain-of-function variants in this gene have been associated with a dominant form of generalized epilepsy and paroxysmal dyskinesia. Here, we genetically and functionally characterize eight novel loss-of-function (LoF) variants of KCNMA1. Genome or exome sequencing and the participation in the international Matchmaker Exchange effort allowed for the identification of novel KCNMA1 variants. Patch clamping was used to assess functionality of mutant BK channels. The KCNMA1 variants p.(Ser351Tyr), p.(Gly356Arg), p.(Gly375Arg), p.(Asn449fs) and p.(Ile663Val) abolished the BK current, whereas p.(Cys413Tyr) and p.(Pro805Leu) reduced the BK current amplitude and shifted the activation curves toward positive potentials. The p.(Asp984Asn) variant reduced the current amplitude without affecting kinetics. A phenotypic analysis of the patients carrying the recurrent p.(Gly375Arg) de novo missense LoF variant revealed a novel syndromic neurodevelopmental disorder associated with severe developmental delay, visceral and cardiac malformations, connective tissue presentations with arterial involvement, bone dysplasia and characteristic dysmorphic features. Patients with other LoF variants presented with neurological and developmental symptoms including developmental delay, intellectual disability, ataxia, axial hypotonia, cerebral atrophy and speech delay/apraxia/dysarthria. Therefore, LoF KCNMA1 variants are associated with a new syndrome characterized by a broad spectrum of neurological phenotypes and developmental disorders. LoF variants of KCNMA1 cause a new syndrome distinctly different from gain-of-function variants in the same gene.

Findings in patients from Benin with osteomyelitis and polymerase chain reaction-confirmed Mycobacterium ulcerans infection.

BACKGROUND: Mycobacterium ulcerans is known to cause Buruli ulcer (BU), a necrotizing skin disease leading to extensive cutaneous and subcutaneous destruction and functional limitations. However, M. ulcerans infections are not limited to skin, and osteomyelitis, still poorly described in the literature, occurs in numerous young patients in Africa. METHODS: In a retrospective matched case-control study conducted in a highly endemic area in Benin, we analyzed demographic, clinical, biological, and radiological features in all patients with M. ulcerans infections with bone involvement, identified from a cohort of 1257 patients with polymerase chain reaction-proved M. ulcerans infections. RESULTS: The 81 patients studied had a median age of 11 years (interquartile range, 7-16 years) and were predominantly male (male-female ratio, 2:1). Osteomyelitis was observed beneath active BU lesions (60.5%) or at a distance from active or apparently healed BU lesions (14.8%) but also in patients without a history of BU skin lesions (24.7%). These lesions had an insidious course, with nonspecific clinical findings leading to delayed diagnosis. A comparison with findings in 243 age- and sex-matched patients with BU without osteomyelitis showed that case patients were less likely to have received BCG immunization than controls (33.3% vs 52.7%; P = .01). They were also at higher risk of longer hospital stay (118 vs 69 days; P = .001), surgery (92.6% vs 63.0%; P = .001), and long-term crippling sequelae (55.6% vs 15.2%; P < .001). CONCLUSIONS: This study highlighted the difficulties associated with diagnosis of M. ulcerans osteomyelitis, with one-fourth of patients having no apparent history of BU skin lesions, including during the current course of illness. Delays in treatment contributed to the high proportion (55.6%) of patients with crippling sequelae.

Risk Factors Associated with Traumatic Brain Injury and Implementation of Guidelines for Requesting Computed Tomography After Head Trauma Among Children in France.

Importance: Pediatric traumatic brain injuries (TBIs) are a leading cause of death and disability. The Pediatric Emergency Care Applied Research Network (PECARN) guidelines provide a framework for requesting head computed tomography (HCT) after pediatric head trauma (PHT); however, quantitative data are lacking regarding both TBIs found on HCT and justification of the HCT request according to the PECARN guidelines. Objectives: To evaluate the types, frequencies, and risk factors for TBIs on HCT in children referred to emergency departments (EDs) who underwent HCT for PHT and to evaluate quality of HCT request. Design, Setting, and Participants: This multicenter, retrospective cohort study included patients younger than 18 years who underwent HCT for PHT who were referred to 91 EDs during on-call hours between January 1, 2020, to May 31, 2022. Data were analyzed between July and August 2022. Exposure: All radiological reports with pathologic findings were reviewed by 4 senior radiologists. Six hundred HCT requests filled by emergency physicians were randomly sampled to review the examination justification according to the PECARN guidelines. Main Outcomes and Measures: Associations between TBIs, age, sex, and Glasgow Coma Scale (GCS) were investigated using univariable χ2 and Cochrane-Armitage tests. Multivariable stepwise binary logistic regressions were used to estimate the odds ratio (ORs) for intracranial hemorrhages (ICH), any type of fracture, facial bone fracture, and skull vault fracture. Results: Overall, 5146 children with HCT for PHT were included (median [IQR] age, 11.2 [4.7-15.7] years; 3245 of 5146 [63.1%] boys). ICHs were diagnosed in 306 of 5146 patients (5.9%) and fractures in 674 of 5146 patients (13.1%). The following variables were associated with ICH in multivariable analysis: GCS score of 8 or less (OR, 5.83; 95% CI, 1.97-14.60; P < .001), extracranial hematoma (OR, 2.54; 95% CI, 1.59-4.02; P < .001), skull base fracture (OR, 9.32; 95% CI, 5.03-16.97; P < .001), upper cervical fracture (OR, 19.21; 95% CI, 1.79-143.59; P = .006), and skull vault fracture (OR, 35.64; 95% CI, 24.04-53.83; P < .001). When neither extracranial hematoma nor fracture was found on HCT, the OR for presenting ICH was 0.034 (95% CI, 0.026-0.045; P < .001). Skull vault fractures were more frequently encountered in children younger than 2 years (multivariable OR, 6.31; 95% CI, 4.16-9.66; P < .001; reference: children ≥12 years), whereas facial bone fractures were more frequently encountered in boys older than 12 years (multivariable OR, 26.60; 95% CI, 9.72-109.96; P < .001; reference: children younger than 2 years). The justification for performing HCT did not follow the PECARN guidelines for 396 of 589 evaluable children (67.2%) for requests filled by emergency physicians. Conclusion and Relevance: In this cohort study of 5146 children who underwent HCT for PHT, knowing the odds of clinical and radiological features for ICHs and fractures could help emergency physicians and radiologists improve their image analysis and avoid missing significant injuries. The PECARN rules were not implemented in nearly two-thirds of patients.