OBJECTIVE: To delineate the clinical and genetic features of a Chinese girl harboring a rare de novo variant of SYNGAP1 associated with Mental retardation, autosomal dominant 5 (MRD5), and to conduct a comprehensive genotype-phenotype correlation analysis within the Chinese population through an extensive literature review. METHODS: A 5-year-old girl presenting with seizures without an obvious cause was enrolled in September 2020. Genomic DNA was extracted from the patient and her parents. Whole exome sequencing (WES) was performed on the proband to identify suspected pathogenic variants based on her clinical phenotype. Sanger sequencing was used for validation, followed by bioinformatic analysis of the variant. Additionally, data from 54 previously reported Chinese cases with SYNGAP1 variants were integrated to summarize the distribution of variant types and clinical characteristics. Ethical approval was obtained from the Ethics Committee of Kunming Children's Hospital (Ethics No.: 2021-03-055-K01). RESULTS: WES identified a heterozygous nonsense variant, SYNGAP1 c.725G>A (p.Trp242*), in the proband. Sanger sequencing confirmed it was a de novo variant. According to the ACMG guidelines, this variant was classified as pathogenic (PVS1+PS2). Based on the clinical manifestations, the patient was diagnosed with MRD5. Bioinformatic analysis suggested that this variant introduces a premature stop codon at tryptophan 242, disrupting the PH domain and leading to the loss of the C2, Ras-GAP, and C-terminal domains. The pooled analysis of Chinese cases revealed that nonsense (38.2%) and frameshift (36.4%) variants were the predominant types. Intellectual disability/developmental delay was present in 100.0% of patients, epilepsy in 83.6%, and autism spectrum disorder in 41.3%. The incidence of epilepsy differed significantly among variant types (P = 0.045). Exons 8 and 15 were identified as mutation hotspots. CONCLUSION This study has identified a SYNGAP1 c.725G>A variant in the Chinese population and confirmed it as a potential cause of MRD5, which expanded the mutational spectrum of this disorder.
Humans ; Female ; Child, Preschool ; Intellectual Disability/genetics* ; ras GTPase-Activating Proteins/genetics* ; Phenotype ; Exome Sequencing ; Genetic Association Studies

WAGR syndrome is a rare congenital disorder, occurring in approximately 1 in 500,000 to 1,000,000 individuals, often presenting with ocular malformations such as aniridia. Glaucoma frequently develops when the iris and angle structures are affected, posing a significant risk of vision loss. We report a one-year and seven-month-old patient who presented with corneal opacity of the left eye. Examination revealed corneal opacity, aniridia, and markedly elevated intraocular pressure of 65 mmHg, while the fellow eye, also with aniridia, was normotensive. The patient underwent immediate combined trabeculectomy-trabeculotomy. Postoperative follow-up and timely management of complications allowed acceptable pressure control over one year, though visual prognosis remained guarded. This case highlights the challenges of managing glaucoma in WAGR syndrome, particularly in resource-limited settings. Medical therapy alone is often insufficient, making surgical intervention essential. Combined trabeculectomytrabeculotomy proved effective in maintaining pressure control when glaucoma drainage devices were not feasible. Multiple interventions and close monitoring are frequently required due to the risk of scarring and postoperative complications. Our experience emphasizes the need for a multidisciplinary ophthalmology approach to optimize outcomes. Despite pressure control, visual outcomes often remain poor due to structural anomalies and the challenges inherent to pediatric patients with this rare syndrome.

Introduction: Endocrine abnormalities are frequently observed in children with Down syndrome, with thyroid dysfunction being the most common. The distribution and patterns of thyroid disorders vary between populations. Methodology: Retrospective data were collected from the electronic medical records of children with Down syndrome who attended the paediatric clinic at University Malaya Medical Centre from the year 2000 to 2025. Data were analyzed to determine the frequency and distribution of thyroid disorders in this cohort. Results: The study included 57 patients, the majority of whom were identified through routine screening (n = 56, 98.2%). Only one child (1.8%) was diagnosed following a symptomatic presentation of diarrhea. Within the cohort, 51 patients were diagnosed with hypothyroidism and six with hyperthyroidism. Among those with hypothyroidism, the mean TSH was 22.5 mIU/L, with a median age at presentation of 61 days (IQR: 19–211.5). Notably, 25% of the cohort presented within the first 19 days, while the rest presented after 7 months of age. Of these, 24 cases (47.1%) were transient, with medications successfully discontinued at a mean age of 4.0 ± 2.13 years. Only 26 patients underwent thyroid scan, which was normal except for one case of thyroid agenesis. Imaging was not performed in others due to early discontinuation of therapy or loss to follow-up. All hyperthyroid patients had autoimmune thyroid disease (4 Graves’ disease, 2 Hashimoto’s thyroiditis) with positive autoantibodies. The median age at presentation was 5.4 years (IQR: 2.3–10.2). Conclusion Screening for thyroid dysfunction successfully identified almost all cases in patients with Down syndrome. Notably, patients which hyperthyroidism in this cohort had co-occurring autoimmune thyroid dysfunction and demonstrated a significantly earlier age of presentation compared to the general paediatric population.
Child ; Down Syndrome ; Thyroid Gland

Introduction: Children with Down syndrome (DS) have a higher prevalence of hypothyroidism compared to the general population, and both conditions are linked to impaired growth. This study aimed to determine the prevalence and subtypes of hypothyroidism in DS and to compare growth outcomes with controls from general population at 2 years of age. Methodology: A retrospective review was conducted on 248 children with DS (aged 2–18 years) followed at Hospital Pakar Universiti Sains Malaysia from 2020 to 2025. Growth outcomes were analyzed in a subgroup of 41 DS children with hypothyroidism compared to 46 controls. Growth was compared using standard CDC charts for and z -scores calculated with PediTools (CDC 2–20 age). Mid-parental height, target height attainment, and height velocity were evaluated. Statistical analysis used t-tests and chi-square tests (p <0.05). Results: Of the 248 children with DS, 63.7% had hypothyroidism, predominantly subclinical (85.4%). No cases of acquired or secondary hypothyroidism were found. Children with DS had significantly lower mean height z-scores (−1.91 ± 1.45 vs. −0.54 ± 1.25; p <0.001), borderline lower height velocity (5.80 ± 2.15 vs. 6.92 ± 3.56 cm/year; p = 0.050), and fewer achieved target height (35% vs. 64.1%; p = 0.030) compared to controls. Baseline characteristics were similar between groups. Thyroid ultrasound showed normal anatomy in 50%, hypoplasia in 28.6%, and nodules in 21.4%. Common comorbidities included congenital heart disease (78.4%), pulmonary complications (16.2%), and other anomalies (32.4%). Conclusion Subclinical hypothyroidism was the predominant subtype in DS. Affected children demonstrated poorer growth, with reduced height z-scores, slower growth velocity, and lower likelihood of achieving target height.
Humans ; Down Syndrome ; Prevalence ; Hypothyroidism

Introduction: ABCD syndrome (ABnormal Calcium-CreatinineCalcinosis in Down syndrome) is a rare tetrad of hypercalcemia, hypercalciuria, nephrocalcinosis, and renal impairment in children with Down syndrome, often with delayed diagnosis resulting in irreversible renal damage. : We report a 7-year-old male with Down syndrome, who previously had a stormy neonatal period due to large atrialseptal-defect and pulmonary hypertension, and required surgery at 3-years-old with prior prolonged ventilation. He was since bedbound with severe spastic diplegia, complicated by GERD and food aversion, requiring nasogastric tube feeding. He was discovered to have hypercalcemia and renal impairment during admission in district hospital for febrile illness with gastrointestinal symptoms. Initial serum calcium was 2.78 mmol/L, phosphate 1.54 mmol/L, magnesium 0.96 mmol/L, ALP 210 IU/L, urea 18.6 mmol/L, and creatinine 266 umol/L. Renal impairment did not improve and ultrasound KUB revealed bilateral small kidneys with medullary nephrocalcinosis. Consultation with the paediatric nephrologist concluded as CKDstage-4. He was transferred to our centre. He demonstrated severe hypercalcemia (3.44 mmol/L), hypercalciuria (urinecalcium-to-creatinine-ratio of 1.17 mmol/mmol, >95 th%), and suppressed iPTH (0.9 pmol/L,1.6–6.9), suggesting PTH-independent process. 25-OH-Vit-D3 was 134 nmol/L (74–250, sufficient). He was more irritable and moody, but no seizures. ECG was normal. Skeletal assessment did not reveal osteolytic changes or increased resorption. He was investigated by paediatric hemato-oncologists, with negative findings, despite extensive search for hematological or bone malignancy and granulomatous disease. His ESR and immunoglobulin level was high for unknown reasons. He was treated with intravenous and oral hydration, dietary calcium restriction with modified lowcalcium formula, assisted by dietitian, and IV pamidronate infusion (0.125 mg/kg) stat dose, resulting in stabilization of serum calcium level (2.5 mmol/L), which persisted for about 8 weeks during follow-up. Conclusion ABCD syndrome should be considered in Down syndrome children presenting with unexplained hypercalcemia. Early recognition and intervention are vital.
ABCD syndrome ; Down Syndrome ; Hypercalcemia

BACKGROUND

Down syndrome or trisomy 21, the most common chromosomal disorder, results from the presence of a third copy of chromosome 21 and manifests as mild to moderate intellectual disability, growth retardation, congenital heart defects, gastrointestinal abnormalities, and characteristic facial features. Several methods have been used to screen for Down syndrome in the prenatal period, such as ultrasound, biomarkers, cell-free DNA testing, and combinations of these tests. A positive result from one or more of these screening tests signals the need for confirmatory karyotyping to clinch the diagnosis. Ultrasound between 11 to 14 weeks of gestation can evaluate nuchal translucency (NT) to screen for Down syndrome. During the second trimester, a triple or quadruple test can also be performed alone or in addition to NT to quantify Down syndrome risk. In limited resource settings however, only the measurement of NT via ultrasound can be performed since biomarker tests are either unavailable or inaccessible. While the diagnostic performance of NT measurement alone has been investigated in several observational studies, there is no consensus on its performance as a sole test to screen for Down syndrome.

To determine the diagnostic performance of NT during prenatal first-trimester ultrasound as a screening test for Down syndrome.

We performed a systematic search on the PubMed, ProQuest, and Cochrane Library databases for recent systematic reviews and meta-analyses that addressed the objective. The existing reviews found were then independently appraised by the two reviewers with the AMSTAR-2 checklist. To update the existing reviews, a systematic search was done in the same databases to identify additional primary diagnostic studies, which were appraised using the QUADAS-2 tool. Random-effects univariate meta-analysis and summary receiving operator curve (HSROC) analysis for the outcomes were performed using Review Manager version 5.4 and R version 4.2.2, respectively. Subgroup analysis was performed by stratifying the baseline risk of mothers for fetal anomaly as low- or high-risk. Highrisk mothers were defined as women with risk factors such as advanced age, positive serum screen, presence of other ultrasound anomalies, and history of previous fetus with anomaly.

We found 22 cohort studies (n=225,846) of women at low-risk for fetal anomaly. The pooled sensitivity was 67.8% (95% CI: 61.4%-73.6%, I2=70.4%) and specificity was 96.3% (95% CI: 95.5%-96.9%, I2=96.7%). For low-risk women, the overall certainty of evidence was low, due to different modes of verification and heterogeneity not completely explained by variability in baseline risk or cut-points. Seven studies (n=9,197) were on high-risk women. The pooled sensitivity was 62.2% (95% CI: 54.1%-69.7%, I2=38.8%) and specificity was 96.5% (95% CI: 93.6%-98.1%, I2=95.5%). For women at high-risk, the evidence was rated as moderate due to differential verification.

Our analysis showed that NT measured through first-trimester ultrasound is specific for Down syndrome but has low sensitivity. Despite this, it is a useful screening test for Down syndrome in low-resource settings where other strategies may not be available or accessible. Furthermore, interpretation of NT results must take into consideration its limited sensitivity as this may lead to missed cases.

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intellectual developmental disorder (IDD), are highly prevalent and lack effective treatments, posing significant health challenges. These disorders are frequently comorbid with disruptions in sleep rhythms, and sleep-related indicators are often used to assess disease severity and treatment efficacy. Recent evidence has highlighted the crucial roles of circadian rhythm disturbances and circadian clock gene mutations in the pathogenesis of NDDs. This review focuses on the mechanisms by which circadian rhythm disruptions and circadian clock gene mutations contribute to cognitive, behavioral, and emotional disorders associated with NDDs, particularly through the dysregulation of dopamine system. Additionally, we discussed the potential of targeting the circadian system as novel therapeutic strategies for the treatment of NDDs.
Humans ; Neurodevelopmental Disorders/genetics* ; Attention Deficit Disorder with Hyperactivity/genetics* ; Circadian Rhythm/genetics* ; Autism Spectrum Disorder/genetics* ; Mutation ; Intellectual Disability/genetics* ; Circadian Clocks/physiology* ; Dopamine/metabolism*

OBJECTIVES: To summarize the clinical manifestations and genetic characteristics of creatine deficiency syndrome (CDS) caused by GAMT gene mutations. METHODS: A retrospective analysis was conducted on the clinical and genetic data of two children diagnosed with GAMT deficiency-type CDS at the Children's Medical Center of Xiangya Hospital, Central South University, from December 2020 to December 2024. RESULTS: The two patients presented with symptoms in infancy, and both had compound heterozygous mutations in the GAMT gene. Case 1 exhibited seizures and intellectual disability, while Case 2 had intellectual disability and attention-deficit hyperactivity disorder. Magnetic resonance spectroscopy of cranial MRI in both patients indicated reduced creatine peaks. After creatine treatment, seizures in Case 1 were controlled, but both patients continued to experience intellectual disabilities and behavioral issues. As of December 2024, a total of 21 cases have been reported in China (including this study), and 115 cases have been reported abroad. All patients exhibited developmental delay or intellectual disabilities, with 66.9% (91/136) experiencing seizures, 33.8% (46/136) presenting with motor disorders, and 36.8% (50/136) having behavioral problems. Seventy-five percent (102/136) of patients received creatine treatment, leading to significant improvements in seizures and motor disorders, although cognitive improvement was not substantial. CONCLUSIONS GAMT deficiency-type CDS is rare and presents with nonspecific clinical features. Timely diagnosis facilitates targeted treatment, which can partially improve prognosis.
Child ; Female ; Humans ; Male ; Creatine/deficiency* ; Guanidinoacetate N-Methyltransferase/deficiency* ; Intellectual Disability/genetics* ; Mutation ; Retrospective Studies ; Rhabdomyolysis/genetics* ; Language Development Disorders ; Movement Disorders/congenital*

OBJECTIVES: To summarize the clinical and genetic characteristics of epilepsy with intellectual disability caused by SETD1B gene variants in children. METHODS: A retrospective analysis was conducted on the clinical data of three children with SETD1B gene variants diagnosed and treated at the Department of Pediatric Neurology of Xiangya Hospital of Central South University. Relevant literature was reviewed to summarize the clinical characteristics of this condition. RESULTS: All three children presented with symptoms during infancy or early childhood, including mild intellectual disability and myoclonic seizures, with two cases exhibiting eyelid myoclonia. After treatment with three or more antiepileptic drugs, two cases achieved seizure control or partial control, while one case remained refractory. Each of the three children was found to have a heterozygous variant in the SETD1B gene (one deletion, one frameshift, and one missense variant). To date, 54 cases with SETD1B gene variants have been reported, involving a total of 56 variants, predominantly missense variants (64%, 36/56). The main clinical manifestations included varying degrees of developmental delay (96%, 52/54) and seizures (81%, 44/54). Among the 44 patients with seizures, myoclonic (20%, 9/44) and absence seizures (34%, 15/44) were common, with eyelid myoclonia reported in six cases. Approximately one-fifth of these patients had poorly controlled seizures. CONCLUSIONS The primary phenotypes associated with SETD1B gene variants are intellectual disability and seizures, and seizures exhibit distinct characteristics. Eyelid myoclonia is not uncommon.
Humans ; Intellectual Disability/complications* ; Epilepsy/complications* ; Male ; Female ; Histone-Lysine N-Methyltransferase/genetics* ; Child, Preschool ; Child ; Retrospective Studies

A 7-year-old girl was admitted to the hospital with rapidly progressive vision loss. Since 1 year of age, she had exhibited developmental delay accompanied by visual impairment and neutropenia. Combined with genetic testing and molecular pathogenicity analysis, she was diagnosed with Cohen syndrome (CS) caused by compound heterozygous variants in VPS13B (c.6940+1G>T and c.2911C>T). The c.6940+1G>T variant resulted in exon 38 skipping, leading to a frameshift and premature termination. Reverse transcription quantitative polymerase chain reaction revealed significantly reduced VPS13B gene expression (P<0.05). Bioinformatic analysis suggested that both variants likely produce truncated proteins. This case highlights that integrating clinical features with molecular pathogenicity assessment (DNA, RNA, and protein analysis) can improve early diagnostic accuracy for CS.
Humans ; Female ; Child ; Vesicular Transport Proteins/genetics* ; Developmental Disabilities/etiology* ; Muscle Hypotonia/etiology* ; Myopia/etiology* ; Heterozygote ; Intellectual Disability/etiology* ; Microcephaly/etiology* ; Obesity/genetics* ; Growth Disorders/etiology* ; Retinal Degeneration/genetics* ; Psychomotor Disorders/genetics* ; Fingers/abnormalities*