Novel mutation c.2090_2091del in neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities in an 18.5-mo-old boy:A case report

BACKGROUND Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities(NECRC)is a rare,autosomal,dominant neurological disorder caused by mutations in the ZMYM2 gene.To date,the clinical and functional characteristics of the novel ZMYM2 mutation c.2090_2091del have not yet been reported.CASE SUMMARY The patient was an 18.5-mo-old Chinese boy with motor and language delay,microcephaly,facial dysmorphism,moderate malnutrition,single palmar crease on the left hand,synpolydactyly of the right foot,hypotonia and feeding problems.The boy who was diagnosed with NECRC was enrolled in the First Affiliated Hospital,Henan University of Chinese Medicine,and his clinical data were collected.From the whole-exon sequencing(WES)data,the pathogenic SNVs/InDels were identified,and the molecular findings were characterized.WES revealed that the heterozygous variant in the ZMYM2 gene was c.2090_20-91del,p.Ser697TrpfsTer3,a frameshift mutation,which is a NECRC-related gene mutation.CONCLUSION We performed a systematic literature review to identify and characterize NECRC.Substantial evidence from the literature indicated that patients with ZMYM2 gene mutation showed different degrees of intellectual disability,motor and language retardation,facial dysmorphism,and a few had congenital heart defects,kidney and urinary tract abnormalities.Early diagnosis and prompt management with comprehensive rehabilitation training are beneficial,but may not improve long-term outcomes.

A Study of Radiation-Induced Instability for the Gene Locus Associated with Intellectual Disorders or Developmental Delays

Multiplex Ligation-Dependent Probe Amplification (MLPA) was used to study the integrity of the chromosomes for two WIL2-derived lymphoblastoid cell lines (TK6 and WTK1) in the presence and absence of ionizing radiation. WTK1 cells contain a p53 mutation, whereas the TK6 cell line has the native p53 tumor-suppressor gene. Each cell line was isolated pre- and post-irradiation (2 and 3 Gy) and analyzed by MLPA. Using probes that target specific regions on chromosomes associated with a distinct subset of microdeletions and microduplications either established or thought to be responsible for intellectual disability or developmental delay, we have demonstrated that WTK1 and TK6 are not impacted in the same way by irradiation. Instead, each cell line presents its own unique MLPA profile. The most notable differences are the appearance of nine unique probe signals only seen in WTK1 cells. These results are important in the study of how different cell lines can be affected in significantly different ways depending on the presence or absence of wild type p53.

Novel frameshift mutation in the AHDC1 gene in a Chinese global developmental delay patient:A case report

BACKGROUND Xia–Gibbs syndrome(XGS,OMIM:615829),caused by mutations within the ATHook DNA-binding motif-containing protein 1(AHDC1)gene(OMIM:615790),located on the short arm of chromosome 1 within the cytogenetic band 1p36.11,contains five noncoding 5 exons,a single 4.9-kb coding exon,and a noncoding 3 exon.CASE SUMMARY In this case report,we diagnosed and treated a 6-mo-old girl with XGS.The primary clinical symptoms included global developmental delay,hypotonia,and mild dysmorphic features.Using high-throughput whole-exosome sequencing to sequence the patient and her parents,and the results showed a novel frameshift mutation of c.1155dupG(p.Arg386Alafs*3)in the AHDC1 gene.The paternal gene was wild type.CONCLUSION This report extends the mutation spectrum of the AHDC1 gene to provide the diagnostic basis for genetic counseling in families with XGS.

Management of Cataracts in Pediatric Patients with Developmental Delay at a Tertiary Care Pediatric Hospital

Background: Childhood cataract causing visual impairment can compound developmental delay (DD) if left untreated. Current literature in children with DD is limited;thus, we evaluated cataract etiology, challenges, and treatment compliance in this group. Purpose: To report the presentation and challenges associated with cataract management in children with developmental delay (DD) at a tertiary care pediatric hospital. Methods: Retrospective review of 100 patients (173 eyes) presenting with cataracts and DD from February 2014 to December 2017. Results: 100 patients (173 eyes) were included. 27 patients had unilateral cataracts and 73 bilateral. The average age was 120.55 months (SD 63.77, range 5.87 - 243.16);the average follow-up period was 57.7 months (SD 139.14, range 1.03 - 1412.30). 61% of patients (55% eyes) underwent medical management for cataracts due to: cataract was not visually significant (66% eyes), parent deferred surgery (11% eyes), self-abusive behavior (14% eyes), and medical conditions that limited visual recovery (9% eyes). 32% of patients were unable to perform objective visual acuity by age 5. Patients with self-abusive behavior were more likely to present with or develop retinal detachment (RD) (35%) compared to those without self-abusive behavior (6%) (p = 0.0028). A statistically significant difference in the difficulty of examination (p < 0.0001) and poor compliance of glasses wear (p < 0.0001) was found in nonverbal patients. Surgical complications occurred in 39% of eyes. Those with intraocular lens placement after cataract extraction were more likely to develop visual axis opacification (27% eyes) than those who remained aphakic (9% eyes) (p = 0.0313). Conclusion: Cataract extraction in pediatric patients with DD can be associated with success, however, providers should prepare for limitations in managing these patients.

The Effects of a Drums Alive^®Kids Beats Intervention on the Physical Performance and Motor Skills of Children with Developmental Delays

The objective of this original pilot study was to determine if the Drums Alive® Kids Beats intervention could provide statistically significant improvements to physical and motor skill performance on participants with Developmental Delays (DD) using the Dusseldorf Motor-Proficiency-Test for children (MOT 4-6) model. The researchers selected the research-based Drums Alive Kids Beat intervention because of its multidisciplinary methodology that in previous studies demonstrated positive effects on physiological, psychological, neurological, educational, rhythmical, and socio-emotional literacy. Facilitators used standardized Drums Alive approved lesson plans and equipment to conduct the intervention through a battery of music, movement and drumming-centered exercises and activities. The 30 participants were German students between 4.9 and 10.2 years of age, without any inclusion or exclusion characteristics, who were divided into three groups consisting of two intervention groups: IG Kindergarten (IG Kinder), IG Elementary (IG Elem) with varied physical, social, and emotional DD that affected gross and fine motor skills, movement, coordination, and behavioral control;and, a Control Group (CG) that had normal physical and motor skill development (Table 1). The results of the study suggested that the Drums Alive Kids Beats intervention provided statistically significant improvements in physical and motor skill performance in children with DD, namely, 24% improvement (IG Kinder), 14% (IG Elem) vice a minor 4% improvement (CG). Of note, during this study to measure physical capability pre- and post-intervention, the facilitators noticed significant improvements in behavior in both IG groups;therefore, they chose to conduct a collateral study to measure six behavioral domains which will be documented in a future publication to demonstrate the exclusive relationship between the Drums Alive Kids Beats intervention and improvement in behavior.

SATB2-associated syndrome caused by a novel SATB2 mutation in a Chinese boy:A case report and literature review

BACKGROUND Special AT-rich sequence binding protein 2(SATB2)-associated syndrome(SAS;OMIM 612313)is an autosomal dominant disorder.Alterations in the SATB2 gene have been identified as causative.CASE SUMMARY We report a case of a 13-year-old Chinese boy with lifelong global developmental delay,speech and language delay,and intellectual disabilities.He had short stature and irregular dentition,but no other abnormal clinical findings.A de novo heterozygous nonsense point mutation was detected by genetic analysis in exon 6 of SATB2,c.687C>A(p.Y229X)(NCBI reference sequence:NM_001172509.2),and neither of his parents had the mutation.This mutation is the first reported and was evaluated as pathogenic according to the guidelines from the American College of Medical Genetics and Genomics.SAS was diagnosed,and special education performed.Our report of a SAS case in China caused by a SATB2 mutation expanded the genotype options for the disease.The heterogeneous manifestations can be induced by complicated pathogenic involvements and functions of SATB2 from reviewed literatures:(1)SATB2 haploinsufficiency;(2)the interference of truncated SATB2 protein to wild-type SATB2;and(3)different numerous genes regulated by SATB2 in brain and skeletal development in different developmental stages.CONCLUSION Global developmental delays are usually the initial presentations,and the diagnosis was challenging before other presentations occurred.Regular follow-up and genetic analysis can help to diagnose SAS early.Verification for genes affected by SATB2 mutations for heterogeneous manifestations may help to clarify the possible pathogenesis of SAS in the future.

PACS gene family-related neurological diseases: limited genotypes and diverse phenotypes

Background The PACS gene family has been demonstrated to be related to intracellular vesicular trafficking.The phenotypic manifestations caused by the pathogenic variants of PACS include epilepsy,intellectual disability/developmental delay,and malformations,such as facial abnormalities.Methods We identified seven new cases with pathogenic or likely pathogenic PACS variants using next-generation sequencing.Detailed information obtained from these patients was analyzed along with that obtained from previously reported patients.Results With the inclusion of the newly diagnosed cases in this study,103 cases with PACS gene family-related neurological diseases were reported,of which 43 were PACS2-related cases and the remaining were PACSI-related cases.Most patients had seizures,which have been reported to be effectively controlled by several types of anti-seizure medications(ASMs).The most efficacious and frequently prescribed ASMs included sodium valproate(43.3%,13/30),oxcarbazepine/carbamazepine(26.7%,8/30),and levetiracetam(20%,6/30).Almost all patients had intellectual disability/developmental delay.The most common pathogenic missense variants were PACSI p.Arg203Trp and PACS2 p.Glu209Lys.In addition,we report a patient carrying a likely pathogenic copy number variation(CNV)(de novo heterozygous deletion of chr14:105821380-106107443,286 kilobase,destroyed part of the furin-binding region domain and the protein structure after it)with more severe and refractory late-onset epilepsy.Conclusions The clinical phenotypes of the different PACS heterozygous missense variants were similar.The pathogenic variant sites of PACSI and PACS2 were quite limited but located in different regions.A CNV destroying part of the PACS2 gene might also be pathogenic.These findings may provide an important clue for further functional studies on the pathogenic mechanism of neurological disorders related to the PACS gene family.

Brain development in children with developmental delay using amide proton transfer-weighted imaging and magnetization transfer imaging

Importance:The process of brain development in children with developmental delay is not well known.Amide proton transfer-weighted(APTw)imaging is a novel molecular magnetic resonance imaging(MRI)technique that can noninvasively detect cytosolic endogenous mobile proteins and peptides involved in the myelination process,and may be useful for providing insights into brain development.Objective:To assess the contribution of amide proton transfer-weighted(APTw)imaging and magnetization transfer(MT)imaging to the evaluation of children with developmental delay(DD).Methods:Fifty-one patients with DD were recruited to this study.The patients were divided into two groups according to the state of myelination assessed on conventional magnetic resonance imaging(MRI).Thirty patients(10 girls,20 boys;age range:1-8 months;median age:4 months)in group A showed delayed myelination on MRI,while 21 patients(3 girls,18 boys;age range:12-36months;median age:25months)in group B showed normal myelination on MRI.Fifty-one age-and sex-matched children with normal developmental quotient(DQ)and normal MRI appearance were recruited as normal controls.Three-slice APTw/MT axial imaging was performed at the level of the centrum semiovale,the basal ganglia and the pons.Quantitative data of the MT ratio(MTR)and APTw were analyzed for multiple brain regions.Independent-samplet-tests were used to compare differences in APTw and MTR signals between the two DD groups and normal controls.Analysis of Covariance was conducted to correct the statistical results.The level of statistical significance was set toP<0.05.Results:For group A,the MTR values were lower in all regions(P=0.004-0.033)compared with the normal controls,while the APTw values were higher in the pons,middle cerebellar peduncle,corpus callosum,frontal white matter,occipital white matter and centrum semiovale(P=0.004-0.040).For Group B,the MTR values were slightly reduced,and the APTw values were slightly increased compared with the normal controls,but the differences were not statistically significant(P>0.05).Interpretation:For DD patients showing signs of delayed myelination on MRI,MTR and APTw imaging can help to diagnose myelination delay by quantifying semi-solid macromolecules and cytosolic endogenous mobile proteins and peptides at a molecular level,providing a new method for comprehensive evaluation of DD.For DD patients with normal myelination on MRI,the clinical values of MTR and APTw imaging remain to be explored.

Age- and gender-dependent obesity in individuals with 16pl1.2 deletion

Recurrent genomic imbalances at 16p 11.2 are genetic risk factors of variable penetrance for developmental delay and autism.Recently, 16pl 1.2（chr16：29.5 Mb-30.1 Mb） deletion has also been detected in individuals with early-onset severe obesity.The penetrance of 16p11.2 deletion as a genetic risk factor for obesity is unknown.We evaluated the growth and body mass characteristics of 28 individuals with 16p11.2 （chr16：29.5 Mb-30.1 Mb） deletion originally ascertained for their developmental disorders by reviewing their medical records.We found that nine individuals could be classified as obese and six as overweight.These individuals generally had early feeding and growth difficulties,and started to gain excessive weight around 5-6 years of age.Thirteen out of the 18 deletion carriers aged 5 years and older（72%） were overweight or obese,whereas only two of 10 deletion carriers（20%） younger than five were overweight or obese.Males exhibited more severe obesity than females.Thus,the obesity phenotype of 16p11.2 deletion carriers is of juvenile onset,exhibited an age- and gender-dependent penetrance. 16p11.2 deletion appears to predispose individuals to juvenile onset obesity and in this case are similar to the well-described Prader-Willi syndrome（PWS）.Early detection of this deletion will provide opportunity to prevent obesity.

Abnormal gait and hypoglycorrhachia in a toddler with seizures

Introduction:Glucose transporter type 1(Glut1)deficiency syndrome is a treatable neurometabolic disorder characterized by seizures,developmental delay,and hypoglycorrhachia.Due to the rareness and non-specific clinical manifestations,it is usually mis-or underdiagnosed.Case presentation:We report the case of a toddler who presented with afebrile epileptic seizures and abnormal gait.Brain imaging and electroencephalogram were normal.Further investigation of the cerebrospinal fluid revealed hypoglycorrhachia that was the clue to the diagnosis of Glut1 deficiency syndrome and the initiation of treatment with ketogenic diet.Conclusion:Our case highlights the importance of lumbar puncture while investigating a child with epileptic seizures and abnormal gait or developmental delay,in order not to miss treatable neurometabolic conditions,such as Glut1 deficiency syndrome.