OBJECTIVE:To explore the clinical and genetic characteristics of two children diagnosed with two rare genetic diseases simultaneously. METHODS:Two children with comorbidity of two genetic diseases due to dual genetic mutations diagnosed at the Third Affiliated Hospital of Zhengzhou University respectively in May 2022 and March 2023 were selected as the study subjects. Clinical and genetic data of the two children were retrospectively analyzed. This study has been approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-062-01). RESULTS:Child 1 was a 2-year-and-4-month-old boy whose clinical manifestations included facial dysmorphism, developmental delay, short stature, microcephaly, cleft palate, cryptorchidism, hypospadias, recurrent infections and immunological abnormalities. Whole exome sequencing revealed that he had harbored a heterozygous c.6595delT (p.Y2199Ifs*65) variant of the KMT2D gene and a heterozygous c.1892G>A (p.R631Q) variant of the PIK3R1 gene. This has led to a dual genetic diagnosis of Kabuki syndrome and PI3Kδ-related immunodeficiency type 36. Child 2 was a 15-year-old girl whose clinical manifestations included epilepsy, Albright's hereditary osteodystrophy, long body trunk, short limbs, hypocalcemia, hyperphosphatemia and hyperparathyroidism. The child also had a family history of short stature. Whole exome sequencing revealed that she had harbored a heterozygous c.2T>C (p.Met1?) variant of the GNAS gene and deletion of exons 2 to 6 of the SHOX gene. The two variants have led to dual diagnose of pseudohypoparathyroidism and X-linked idiopathic short stature. CONCLUSION:When the clinical phenotype of a genetic disease is complex and cannot be fully explained with a single genetic variant, multiple pathogenic variants should be considered, and this may lead to the diagnosis of co-morbid genetic diseases. To adopt or supplement corresponding genetic testing in time and re-analyze the genetic data may facilitate accurate diagnosis of co-morbid genetic diseases.

Background Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia (NEDSCAC), induced by MED27 gene, is an autosomal recessive rare disorder characterized by widespread developmental delay with varying degrees of intellectual impairment. Other symptoms include limb spasticity, cataracts, and cerebellar hypoplasia. So far there have been limited reports on NEDSCAC. Methods In this study, we conducted genetic testing on a child presenting with developmental delay as the primary clinical feature. The genetic test results indicated the presence of novel homozygous missense variants c.74G>A, p.(Arg25His) in the MED27 gene. In vitro functional validation experiments, including plasmid construction and cell transfection, Western blotting, and molecular dynamics structural modeling, were performed on the MED27 Arg25His variant. Results The results demonstrated a significant reduction in protein expression of MED27 Arg25His and indicated may weaken the interaction force between the MED27 subunit and MED14 subunit. Conclusions This study expands our understanding of MED27 gene variants and their associated clinical phenotypes. Additionally, it contributes to the investigation of the potential pathogenesis of NEDSCAC caused by MED27 gene variants.

Objective:To explore risk factors for clinical onset in children with uncontrolled self-limited epilepsy with centrotemporal spikes (SeLECTS) managed by 2 anti-seizure medications (ASMs).Methods:A total of 112 children with SeLECTS who were diagnosed at the Department of Pediatric Neurology of the Third Affiliated Hospital of Zhengzhou University from January 2018 to May 2021 were retrospectively reviewed.All of them were treated with conventional ASMs, and regularly followed up for 1-2 years.Types of therapeutic drugs, clinical seizure control status, presence of new seizure forms, electroencephalogram (EEG) were reviewed at follow-up visits.According to whether the seizures were controlled after the use of no more than 2 ASMs, patients were divided into poor response group (43 cases) and good response group (69 cases), and their clinical data and EEG characteristics were compared.Multivariate Logistic regression analysis was used to explore the risk factors for seizures that were uncontrolled by 2 ASMs. Results:There were significant differences in the age of onset ( χ2=8.919, P=0.003), seizure form ( χ2=4.218, P=0.040), seizure frequency ( Z=-7.664, P<0.001), EEG background slowing ( χ2=10.284, P=0.001), emergence of electrical status epilepticus during slow-wave sleep (ESES)( χ2=11.921, P=0.001), discharge generalization ( χ2=25.377, P<0.001), and presence of epileptic encephalopathy with spike-and-wave activation in sleep (EE-SWAS)( χ2=54.334, P<0.001) between groups.Multivariate Logistic regression analysis showed that seizure frequency ( P<0.001, OR=0.086, 95% CI: 0.022-0.329), discharge generalization ( P=0.006, OR=9.942, 95% CI: 1.918-51.527) and EEG background slowing ( P=0.041, OR=6.648, 95% CI: 1.077-41.038) were the 3 main risk factors associated with poor response to short-term medications of ASMs. Conclusions:Seizures are easily controlled in most SeLECTS patients medicated with ASMs with a favorable prognosis.Seizure frequency, discharge generalization and EEG background slowing are risk factors for the poor response to short-term pharmacotherapy in children with SeLECTS.

Objective:To summarize the clinical characteristics of drug-resistant epilepsy (DRE) in children and to analyze the efficacy of lamotrigine (LTG) add-on therapy for DRE in children of different seizure type, syndrome and etiological category.Methods:All cases of DRE patients treated with LTG or other antiseizure medication (ASM) adjunctive therapy in the Third Affiliated Hospital of Zhengzhou University from May 2019 to April 2020 were collected.The LTG add-on therapy group was treated with LTG add-on therapy, and the control group was treated with other ASM add-on therapy.The therapeutic effects of the two groups were compared.Results:A total of 134 cases meeting the requirement of research were collected, including 98 cases in the LTG add-on therapy group and 36 cases in the control group.For seizure of focal onset and unknown origin, there was statistical difference in efficacy between the LTG add-on therapy group and the control group ( Z=-2.48、-2.11, P<0.05), but for generalized DRE in children, there was no statistical difference in efficacy between the two groups ( Z=-0.39, P>0.05). There was a significantly statistical difference in curative effect between the LTG add-on therapy group and the control group for childhood DRE which could not be classified as any epileptic syndrome ( Z=-3.99, P<0.01), but there was no statistical difference in efficacy between the two groups for West syndrome and benign epilepsy accompanied by central temporal spikes ( Z=-0.94、-1.22, P>0.05). For childhood intractable epilepsy with unknown etiology, there was statistical difference in efficacy between the LTG add-on therapy group and the control group ( Z=-1.96, P<0.05), and for childhood intractable epilepsy with structural etiology, there was significantly statistical difference in efficacy between the two groups ( Z=-3.07, P<0.01), but there was no statistical difference in the efficacy for childhood intractable epilepsy with genetic etiology between the two groups ( Z=-1.02, P>0.05). Conclusion:The efficacy of LTG add-on therapy is significantly better than others for childhood DRE with seizure of focal onset or unknown origin, childhood DRE unclassified to any syndrome, and childhood DRE with structural etiology and unknown origin, especially with structural etiology.