Intrauterine chromium exposure and cognitive developmental delay: The modifying effect of genetic predisposition.

There is limited evidence on the effects of intrauterine chromium (Cr) exposure on children's cognitive developmental delay (CDD). Further, little is known about the genetic factors in modifying the association between intrauterine Cr exposure and CDD. The present study involved 2361 mother-child pairs, in which maternal plasma Cr concentrations were assessed, a polygenic risk score for the child was constructed, and the child's cognitive development was evaluated using the Bayley Scales of Infant Development. The risks of CDD conferred by intrauterine Cr exposure in children with different genetic backgrounds were evaluated by logistic regression. The additive interaction between intrauterine Cr exposure and genetic factors was evaluated by calculating the relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (SI). According to present study, higher intrauterine Cr exposure was significantly associated with increased CDD risk [each unit increase in ln-transformed maternal plasma Cr concentration (ln-Cr): adjusted OR (95 % CI), 1.18 (1.04-1.35); highest vs lowest quartile: adjusted OR (95 % CI), 1.57 (1.10-2.23)]. The dose-response relationship of intrauterine Cr exposure and CDD for children with high genetic risk was more prominent [each unit increased ln-Cr: adjusted OR (95 % CI), 1.36 (1.09-1.70)]. Joint effects between intrauterine Cr exposure and genetic factors were found. Specifically, for high genetic risk carriers, the association between intrauterine Cr exposure and CDD was more evident [highest vs lowest quartile: adjusted OR (95 % CI), 2.33 (1.43-3.80)]. For those children with high intrauterine Cr exposure and high genetic risk, the adjusted AP was 0.39 (95 % CI, 0.07-0.72). Conclusively, intrauterine Cr exposure was a high-risk factor for CDD in children, particularly for those with high genetic risk. Intrauterine Cr exposure and one's adverse genetic background jointly contribute to an increased risk of CDD in children.

The diagnostic yield of genetic and metabolic investigations in syndromic and nonsyndromic patients with autism spectrum disorder, global developmental delay, or intellectual disability from a dedicated neurodevelopmental disorders genetics clinic.

First-tier genetic investigations for patients with neurodevelopmental disorders (NDDs) may include chromosomal microarray, Fragile X testing, and screening for inherited metabolic diseases, but most remain undiagnosed upon completion of testing. Here, we report the diagnostic yields of genetic testing for 537 patients with at least one of autism spectrum disorder, global developmental delay, and/or intellectual disability. Patients were assessed in a single neurodevelopmental genetics clinic, and each underwent a standardized history and physical examination. Each patient was characterized as syndromic or nonsyndromic based on clinical features. Our results demonstrate that multigene sequencing (with an NDD gene panel or exome) had a higher diagnostic yield (8%; 95% confidence interval [CI]: 5%, 13%) than chromosomal microarray and Fragile X testing combined (4%; 95% CI: 3%, 7%). Biochemical screening for inherited metabolic diseases had a diagnostic yield of zero. The diagnostic yield of genetic testing was significantly higher for syndromic patients than for nonsyndromic patients (odds ratio [OR] 3.09; 95% CI: 1.46, 6.83) and higher for female patients than for male (OR 3.21; 95% CI: 1.52, 6.82). These results add to the growing evidence supporting a comprehensive genetic evaluation that includes both copy number analysis and sequencing of known NDD genes for patients with NDDs.

Identification of a novel METTL23 gene variant in a patient with an intellectual development disorder: a literature review and case report.

METTL23 belongs to a family of protein lysine methyltransferases that methylate non-histone proteins. Recently, the METTL23 gene has been reported to be related to an intellectual developmental disorder, autosomal recessive 44. Patients present with developmental delay, intellectual disability (ID), and variable dysmorphic features. Here, we report on a Chinese girl who presented with global developmental delay, abnormal brain structure, and multiple facial deformities, including a short/upturned nose with a sunken bridge, thin lips, and flat occiput. Whole-exome sequencing identified a novel variant (NM_001080510.5: c.322+1del) on the METTL23 gene. This variant was not collected on public human variants databases such as gnomAD, predicted to influence the splicing as a classical splicing variant, and classified as Pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Since patients with METTL23-related ID are rare, we summarize and compare the clinical phenotype of reported patients with METTL23 variants. Our report further expands the METTL23 variants and provides new evidence for clinical diagnosis of METTL23-related ID.

Mutated neuron navigator 3 as a candidate gene for a rare neurodevelopmental disorder.

BACKGROUND: Neuron navigator 3 (NAV3) is characterized as one of the neuron navigator family (NAV1, NAV2, NAV3) proteins predominantly expressed in the nervous system. The NAV3-encoded protein comprises a conserved AAA and coiled-coil domains characteristic of ATPases, which are associated with different cellular activities. METHODS: We describe a Saudi proband presenting a complex recessive neurodevelopmental disorder (NDD). Whole exome sequencing (WES) followed by Sanger sequencing, 3D protein modeling and RT-qPCR was performed. RESULTS: WES revealed a bi-allelic frameshift variant (c.2604_2605delAG; p.Val870SerfsTer12) in exon 12 of the NAV3 gene. Furthermore, RT-qPCR revealed a significant decrease in the NAV3 mRNA expression in the patient sample, and 3D protein modeling revealed disruption of the overall secondary structure. CONCLUSION: For the time, we associate a bi-allelic variant in the NAV3 gene causing NDD in humans.

[NFIX gene mutation causes Marshall-Smith syndrome in a pair of identical twins and literature review]. / NFIXåŸºå› å˜å¼‚å¯¼è‡´ä¸€å¯¹åŒåµåŒèƒžèƒŽMarshall-Smithç»¼åˆå¾å¹¶æ–‡çŒ®å¤ä¹ .

This article reports on the clinical and genetic characteristics of monozygotic twins with Marshall-Smith syndrome (MRSHSS) due to a mutation in the NFIX gene, along with a review of related literature. Both patients presented with global developmental delays, a prominent forehead, shallow eye sockets, and pectus excavatum. Genetic testing revealed a heterozygous splicing site mutation c.697+1G>A in both children, with parents showing wild-type at this locus. According to the guidelines of the American College of Medical Genetics and Genomics, this mutation is considered likely pathogenic and has not been previously reported in the literature. A review of the literature identified 32 MRSHSS patients with splicing/frameshift mutations. Accelerated bone maturation and moderate to severe global developmental delay/intellectual disability are the primary clinical manifestations of patients with MRSHSS. Genetic testing results are crucial for the diagnosis of this condition.

A scoping review of early childhood support for Aboriginal and Torres Strait Islander children living with a disability in regional, rural and remote settings.

INTRODUCTION: Many experts and communities have concerns about how National Disability Insurance Scheme services are provided to Aboriginal and Torres Strait children. This study was undertaken at the request of the NPY Women's Council in partnership with the researchers, to explore supports for Aboriginal and Torres Strait Islander children living with a disability in their remote areas. OBJECTIVE: This scoping review aims to (a) explore the barriers and enablers to accessing disability support services for families of young Aboriginal and Torres Strait Islander children (0-8 years) living in regional, rural and remote settings, and (b) summarise best practice approaches for accessing support for young children in these settings. DESIGN: The search was run in three electronic databases, as well as grey literature sources. We assessed the quality of included publications using the Centre of Research Excellence in Aboriginal Chronic Disease Knowledge Translation and Exchange tool. A narrative synthesis was supported by thematic analysis. FINDINGS: From an initial search (557 citations), we identified 13 eligible documents. Most documents were peer-reviewed articles of qualitative studies. Key themes identified included the following: (1) Holistic approach, (2) Understanding disability, (3) Consistent relationships, (4), Flexibility, (5) Simplify system and (6) Enhance communication. DISCUSSION/CONCLUSION: This scoping review has revealed gaps in the provision of quality, culturally responsive disability services for families of Aboriginal and Torres Strait Islander children living in regional, rural and remote areas of Australia. A family-centred, flexible approach will help address their needs. Future research is required to design and evaluate models of care for Aboriginal and Torres Strait Islander children.

Identification of novel variants in BRF1 gene from patient with developmental delay, hearing abnormality, and nervous system anomalies.

Cerebellofaciodental syndrome characterized with dysmorphic features, intellectual disability, and brain anomalies. Now its clinical spectrum expanded more manifestations including bilateral sensorineural hearing impairment and inner ear malformation. Here, we report a 14-month-old boy with global developmental delay and hearing disorder. Whole exome sequencing (WES) revealed the compound heterozygous variants [NM_001519.4: c.652 T > G (p.W218G); c.915 + 1G > T] in the BRF1 gene which inherited from his parents, respectively. The MRI results showed hypoplastic cerebellar vermis, enlarged cisterna magna, and prominent fourth ventricle, the rehabilitation therapy failed to improve the symptoms for our patient. Our finding expands the genetic spectrum of BRF1 variants, which indicates patients with the developmental delay caused by BRF1 variants require other treatments instead of rehabilitation.

The de novo missense mutation F224S in GABRB2, identified in epileptic encephalopathy and developmental delay, impairs GABAAR function.

Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABAAR) have been found to cause neurodevelopmental disorders and epileptic encephalopathy. In a patient with epilepsy and developmental delay, a de novo heterozygous missense mutation c.671 T > C (p.F224S) was discovered in the GABRB2 gene, which encodes the ß2 subunit of GABAAR. Based on previous studies on GABRB2 variants, this new GABRB2 variant (F224S) would be pathogenic. To confirm and investigate the effects of this GABRB2 mutation on GABAAR channel function, we conducted transient expression experiments using GABAAR subunits in HEK293T cells. The GABAARs containing mutant ß2 (F224S) subunit showed poor trafficking to the cell membrane, while the expression and distribution of the normal α1 and γ2 subunits were unaffected. Furthermore, the peak current amplitude of the GABAAR containing the ß2 (F224S) subunit was significantly smaller compared to the wild type GABAAR. We propose that GABRB2 variant F224S is pathogenic and GABAARs containing this ß2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy.

A Germline ZFX Missense Variant in a Patient With Primary Hyperparathyroidism.

A 51-year-old woman with a history of primary hyperparathyroidism (PHPT) with prior parathyroidectomy, osteoporosis, and learning disability was referred for hypercalcemia discovered after a fall. Family history was negative for PHPT, pituitary, enteropancreatic neuroendocrine, or jaw tumors. Dysmorphic facies, multiple cutaneous melanocytic nevi, café au lait macules, long fingers, and scoliosis were observed. Laboratory evaluation showed an elevated parathyroid hormone (PTH) level, hypercalcemia, and hypophosphatemia, all consistent with PHPT. Preoperative imaging revealed a right inferior candidate parathyroid lesion. The patient underwent right inferior parathyroidectomy with normalization of PTH, calcium, and phosphorus. Genetic testing showed a likely pathogenic de novo heterozygous germline missense variant p.R764W in the ZFX gene that encodes a zinc-finger transcription factor previously shown to harbor somatic missense variants in a subset of sporadic parathyroid tumors. Germline variants in ZFX have been reported in patients with an X-linked intellectual disability syndrome with an increased risk for congenital anomalies and PHPT. Further research may determine if genetic testing for ZFX could be of potential benefit for patients with PHPT and developmental anomalies, even in the absence of a family history of parathyroid disease.

Neurodevelopmental Outcomes of Preschoolers with Antenatal Zika Virus Exposure Born in the United States.

Neurodevelopmental outcomes for preschool-age children in the United States with in utero Zika virus (ZIKV) exposure have not yet been reported. We performed a case-control study to assess whether children exposed in utero to ZIKV have abnormal neurodevelopment at age 4-5 years compared to unexposed controls. Thirteen ZIKV-exposed cases that did not have microcephaly or other specific features of congenital Zika syndrome and 12 controls were evaluated between ages 4-5 years. Child neurodevelopment was assessed using the Pediatric Evaluation of Disability Inventory, Behavior Rating Inventory of Executive Function, Peabody Picture Vocabulary Test, Bracken School Readiness Assessment (BSRA), and Movement Assessment Battery for Children (MABC). Caregivers answered questions on the child's medical history and family demographics. Cases and controls were evaluated at mean (SD) ages 4.9 (0.3) and 4.8 (0.4) years, respectively. Caregivers reported more behavior and mood problems in cases than controls. MABC scores showed more gross and fine motor coordination difficulties among cases than controls. Controls trended towards higher performance on concepts underlying school readiness on BSRA. Three cases had a diagnosis of autism spectrum disorder or global developmental delay. Continued follow-up through school age for children with prenatal ZIKV exposure is needed to understand the impact of in utero ZIKV exposure on motor coordination, cognition, executive function, and academic achievement.

Cognitive facet and paradigm of the caregivers of children with developmental problems in Eastern India.

Background: The role of caregivers in grooming the neuro-developmental outcome of high-risk newborns and developmental challenges in children needs to be explored. Objectives: To find the knowledge and perception among parents regarding the neuro-developmental outcome of high-risk newborns, methods adopted to address these problems, and to identify areas on which awareness generation needs to focus. Materials and Methods: A questionnaire-based awareness survey was conducted to understand the knowledge, attitude, and practices of families of children with developmental challenges. Results: The study revealed that more than 70 percent of families lack information about child development, developmental challenges, and means to deal with them. They are unaware of the available health care services and other resources. One in three families has misconceptions on developmental disabilities; consider them as curse or jinx and consequently neglected. Female children with developmental problems are further ostracized due to gender inequity in families. About 10 percent of families have shown great openness toward acquiring new skills and knowledge for handling their children with developmental delays. Conclusions: This study is based on the précis research findings of our grass-root level fieldwork conducted in remote rural Bengal areas. The observation will be of interest and learning materials for general primary care practitioners, family physicians, and stakeholders to initiate appropriate intervention strategies for properly rehabilitating children with developmental delay at grass-root levels of primary health care.

Effect of a Tailored Physiotherapy Rehabilitation on Developmental Delay Primary to Non-communicating Hydrocephalus: A Case Study.

This case report presents the physiotherapy intervention of a one-year-old male child diagnosed with non-communicating hydrocephalus primary to developmental delay. Hydrocephalus is marked by an accumulation of cerebrospinal fluid and often leads to significant developmental delays and neurological impairments in affected infants. The physiotherapy intervention aimed to achieve head and trunk control, improve sensory awareness, and enhance overall body coordination and balance. Various techniques, including neurodevelopmental techniques, sensory stimulation, hippotherapy, and sensory integration therapy, were utilized to target specific developmental milestones and functional abilities. Outcome measures, including the Gross Motor Function Measure, Infant Neurological International Battery, Hammersmith Infant Neurological Examination, and New Ballard Score, were used to assess the patient's progress pre- and post-intervention. Significant improvements were observed across all outcome measures following four months of physiotherapy rehabilitation. The patient demonstrated substantial gains in gross motor function, neurological examination scores, and overall developmental milestones. These findings underscore the effectiveness of physiotherapy rehabilitation in addressing developmental delays associated with non-communicating hydrocephalus. This case underscores the significance of early physiotherapy intervention, which plays a vital role in enhancing outcomes and improving the quality of life for affected children.

Development of a culturally enhanced caregiver-facilitated language nutrition intervention "+Language is Medicine" to address developmental delay in Diné (Navajo) toddlers.

Introduction: Developmental Delay (DD) is highly common in American Indian and Alaska Native (AI/AN; Indigenous) toddlers and leads to high numbers of AI/AN children who eventually need special education services. AI/AN children are 2.89 times more likely to receive special education compared to other children in the U.S., yet developmental disorders are more frequently under diagnosed and untreated in AI/AN infants and toddlers. DD, which can be identified as early as toddlerhood, can lead to negative impacts on developmental trajectories, school readiness, and long-term health. Signs of DD can be identified early with proper developmental screening and remediated with high quality early intervention that includes effective parent training. There are many evidence-based language facilitation interventions often used in Early Intervention programs. However, in communities in rural parts of the Navajo Nation where there are limited services and resources, infants and toddlers with early signs of DD are often missed and do not get the culturally responsive support and evidence-based intervention they deserve. Methods: The community-based +Language is Medicine (+LiM) study team partnered with tribal home visitors, community members, and a Diné linguist/elder using a collaborative virtual workgroup approach in 2021 and 2022 to present the +LiM pilot study aims and to discuss strategies for enhancing a language intervention for toddlers experiencing DD in their tribal community. This paper will detail the stages of community engagement, intervention enhancement and preparation for field testing of the +LiM intervention to address elevated rates of DD in toddlers in the Northern Agency of the Navajo Nation. Results: Two major outcomes from this collaborative workgroup included: (1) a team-initiated redefining of language nutrition to align with Indigenous values that center cultural connectedness and native language use and (2) a five-lesson caregiver-facilitated curriculum titled +Language is Medicine which includes caregiver lessons on language nutrition, language facilitation, shared book reading, pretend play, and incorporation of native language into home routines. These two workgroup outcomes were leveraged to develop a pilot pre-/post-intervention study to test the effectiveness of the +LiM intervention with caregiver-toddler dyads living on the Navajo Nation. Discussion: Delivering tailored child interventions through tribal home visiting are cost-effective and innovative methods for reaching reservation-based families who benefit from culturally responsive parent coaching and instruction. The +LiM team has applied a precision tribal home visiting approach to enhance methods of early intervention for children with DD. Our enhancement process was grounded in Indigenous community-based participatory research that centered culture and language.

Pontocerebellar Hypoplasia Type 9: A Case Study Highlighting Distinctive Magnetic Resonance Imaging Features.

Pontocerebellar hypoplasia type 9 (PCH9) is a rare, autosomal, recessive, neurodevelopmental disorder caused by a mutation in the AMPD2 gene. Despite its rarity, it presents distinctive clinical and neuroradiological features. Diagnosing it is challenging yet crucial for appropriate management. We describe a 21-month-old boy with clinical and neuroradiological manifestations of the diagnosis, including characteristic signs such as an eight-configured midbrain and hypoplasia of the brainstem and cerebellar structures. Genetic evaluation confirmed homozygous missense mutations in the AMPD2 gene. This case highlights the pathognomonic neuroradiological features of pontocerebellar hypoplasia type 9 that point toward diagnosis.

First report of Coffin-Siris Syndrome with SMARCB1 variant, normal intelligence and mild selective neuropsychological deficits: A case report and literature review.

Background: The SMARCB1 gene encodes a subunit of the BRG1-Associated Factor (BAF) complex, and mutations in this gene have been linked to Coffin-Siris Syndrome (CSS) type 3. CSS is characterized by a range of developmental disabilities, facial dysmorphic features, and feeding difficulties. There's been noted genotype-phenotype correlation in CSS, with cases involving SMARCB1 mutations often exhibiting more severe language impairment and intellectual disability. Method: We conducted a review of reported CSS type 3 cases and presented the first instance of CSS associated with a SMARCB1 variant wherein the patient exhibited normal intelligence and only mild selective neuropsychological deficits. The patient underwent evaluation for feeding challenges, growth delay, and dysmorphic features during their second year of life. Subsequently, CSS diagnosis was confirmed due to a de novo heterozygous c.568C > T (p.Arg190Trp) variant in the SMARCB1 gene. Due to learning difficulties, the patient underwent a comprehensive neuropsychological assessment, which was related to the retrospective reconstruction of her medical and developmental history. Results: The patient demonstrated normal intelligence and adaptive functioning, with specific deficits in arithmetic and selective difficulties in verbal learning and long-term memory. Feeding difficulties and language delay observed in early childhood showed significant improvement over time. Discussion: We discuss this case in relation to previously reported CSS type 3 cases, emphasizing neuropsychological aspects. It's evident that neuropsychological features of CSS can vary among affected individuals, highlighting the importance of personalized support and interventions tailored to specific cognitive and emotional needs by healthcare professionals. Our case suggests avenues for future research to identify specific modifiers of phenotypic expression to explain variability in intellect among patients and pinpoint potential targets for gene therapy.

A Rare Case of Niemann-Pick Disease Type-A.

Niemann-Pick disease is a rare lysosomal storage, autosomal recessive disorder that impairs the body's ability to metabolize fats, thus leading to accumulation within cells. It can affect various organs, most commonly the brain, liver, spleen, bone marrow and lungs. Hepatosplenomegaly, inability to thrive and varying neurological deficits are the defining features. The three main types of Niemann-Pick disease are: NPD-A (Niemann-Pick disease type A), NPD-B (Niemann-Pick disease type B) and NPD-C (Niemann-Pick disease type C). NPD-A and NPD-B are due to enzyme acid sphingomyelinase deficiency, caused by SMPD-1 (Sphingomyelin phosphodiesterase 1) gene mutation and NPD-C is due to NPC-1 and NPC-2 (Niemann-Pick C1 and C2 protein) gene mutation. This is the case report of an 11-month-old infant who presented to OPD (Outpatient Department) with failure to thrive, abdominal distension and developmental delay. On examination the infant was emaciated, pale, had hepatosplenomegaly and developmental delay. Bone marrow and liver biopsy showed characteristic lipid-laden foamy macrophages. Thus detailed history, examination and investigations confirmed NPD-A. NPD-A has a poor prognosis and is usually fatal by three years of age. The patient was provided supportive treatment like nutritional therapy and physiotherapy, and parents were counselled regarding the disease outcome. The patient is regularly followed up, and two episodes of chest infections were reported during an 8-month period of follow-up.

Developmental delay in a community setting: Role of a primary care physician.

The early part of childhood especially the first 1000 days plays an essential role in the growth and development of the child. Various internal and external factors affect the child's development, including genetic factors, socioeconomic status, sociocultural environment, maternal mental health, and the parenting environment. There is a high prevalence of developmental delay 17.6% globally, whereas in India, it is around 6.6%. Numerous screening tools are available to detect developmental delay in the child early. Early identification and intervention are crucial because we can have a better outcome for the child if intervention is performed on time. The children can be identified during the postnatal follow-up period. Literature has shown that few parents take their children for regular developmental assessment after delivery. Identifying the developmental impairment early from a primary care physician's point of view is essential. In India under the Rashtriya Bal Swasthya Kariyakram (RBSK), the children are screened at home, Anganwadi centers, and schools to detect at-risk children under 4D's, so that early intervention can be planned by linking them to District Early Intervention Center.

The Effect of Physiotherapy Intervention on an Infant With Congenital Heart Defect Associated With Developmental Delay: A Case Report.

Congenital heart defects (CHDs) are one of the most prevalent anomalies present at birth globally. Children with CHD often face developmental challenges, including motor, language, and cognitive impairments. This case report presents the clinical profile of a 1.2-year-old female child with CHD and developmental delay (DD) post-CHD surgery. The child exhibited delayed gross motor, fine motor, language, and personal-social milestones, along with significant cardiac anomalies observed on CT angiograms. Physiotherapy interventions were initiated to address these DDs, encompassing manual techniques, neurodevelopmental treatment, and multimodal stimulation. The objective of this study was to assess the impact of physiotherapy interventions on improving developmental outcomes in infants with CHD-associated DD. The New Ballard Score and Hammersmith Infant Neurological Examination were utilized to evaluate improvements post-intervention. Significant enhancements in developmental outcomes were observed. This case underscores the significance of holistic care approaches in mitigating the impact of CHD on developmental trajectories and improving the quality of life for affected children.

Developmental Assessment in Children at Higher Likelihood for Developmental Delays - Comparison of Parent Report and Direct Assessment.

PURPOSE: Accurate assessment of cognitive development of young children is a vital component of developmental evaluations. Direct assessment of developmental skills is not always feasible, but there is limited information on the agreement between direct assessment and caregiver-reported cognitive skills. There is limited information regarding the accuracy of the parent-reported Developmental Profile 4 (DP-4) in comparison to the widely-used developmental measure, the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4). The purpose of the current study was to evaluate whether a standardized parent interview can effectively identify children at risk for cognitive developmental delays. METHODS: We compared the agreement between the Bayley-4 Cognitive and the Developmental Profile 4 (DP-4) in young children being evaluated in-person for early developmental delays. 182 children (134 with an autism diagnosis), ages 6-42 months, completed both assessments. RESULTS: Results showed that Bayley-4 Cognitive scores had a moderately strong correlation with DP4-Cognitive scores (r = 0.70, p < 0.001). A cutoff of 70 or 69 on the DP-4 Cognitive was determined as ideal for identifying developmental delay based on diagnosis of global developmental delay or the Bayley-4 Cognitive. CONCLUSIONS: Our analyses revealed good agreement between DP-4 and Bayley-4 Cognitive scores, even after controlling for confounding variables such as degree of ASD characteristics, age, and sex. These results suggest that caregiver-report measures can be a valid and useful tool in the assessment of young children, particularly when direct developmental assessment is not feasible.

Case Report: New presentation of CLIFAHDD syndrome with a novel variant in the NALCN gene and a literature review.

Background: Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome (OMIM #616266) is an autosomal dominant hereditary disease that can lead to the congenital contracture of the limbs and face, hypotonia, and developmental delay. In addition, it may result in growth retardation and present various clinical symptoms, such as brain atrophy, a small pituitary gland, musculoskeletal abnormalities, abnormal breathing, abdominal hernia, and abnormal facial features. Herein, we describe a novel de novo missense genetic variant in the sodium leak channel, non-selective (NALCN) gene that is associated with CLIFAHDD syndrome. Case description: This study describes a patient with varus deformities in both feet, deviation of the ulnar side of the fingers, and severe hypotonia. This patient was subsequently confirmed to have CLIFAHDD syndrome through genetic testing, which also revealed a novel missense de novo genetic variant in the NALCN gene (c.3553G > A, p.Ala1185Thr). Conclusions: Our findings further enrich the known variant spectrum of the NALCN gene and may expand the range of clinical options for treating NALCN-related disorders.