Limb Anomalies Research Articles

Phenotype-to-Genotype Description of Prenatal Suspected and Postnatal Discovered Upper Limb Anomalies: A Retrospective Cohort Study.

To evaluate phenotype and genotype characteristics of fetuses and children with upper limb anomalies. Retrospective cohort study of a prenatal and postnatal cohort with upper limb anomalies from January 2007 to December 2021 in a Fetal Medicine Unit. Prenatally on ultrasound suspected upper limb anomalies, such as transverse and longitudinal reduction defects, polydactyly, and syndactyly, and postnatally identified children referred to the Congenital Hand Team were evaluated separately. The prenatal group included 199 pregnancies: 64 transverse and 19 longitudinal reduction defects, 103 polydactylies, and 13 cases with syndactyly. The majority of cases with longitudinal reduction defects (n=10, 52.6%), polydactyly (n=62, 60.2%), and syndactyly (n=10, 76.9%) were non-isolated, as opposed to transverse reduction defects, which were generally isolated (n=41, 64.1%). The postnatal cohort included 362 children with upper limb anomalies with 49 transverse and 22 longitudinal reduction defects, 226 polydactylies, and 65 syndactylies. Chromosomal or monogenic abnormalities were identified in 76/199 (38.2%) cases of the prenatal cohort and in 31/362 (8.6%) cases of the postnatal cohort. Prenatal identification of minor defects of the digits is a challenge, with more postnatal than prenatal cases. The majority of cases with isolated anomalies in both groups had no underlying chromosomal or monogenic cause, nor were they associated with a syndrome, as compared to the non-isolated cases. Conducting structural anomaly scans and genetic counseling are crucial to assess the risk of genetic abnormalities.

Management of Smith-Lemli-Opitz Syndrome Type II associated with Cleft Palate

Rationale: This case report presents the management of a patient with the rare occurrence of SmithLemli-Opitz Syndrome (SLOS) and complete cleft palate Patient Concerns: The patient's cleft palate repair was not done in infancy, and she reported to the dental institution complaining of difficulty with proper food intake and speech. A clinical examination revealed muscle deformity, limited neck mobility, scoliosis, malocclusion, and inadequate oral health. The patient exhibited facial and limb anomalies characteristic of SLOS, in tandem with substantial challenges in speech and nutrition due to the cleft palate. Diagnosis: The patient was referred to the dental wing to manage the cleft palate defect. On dental examination a complete cleft of the hard and soft palate, which had not been surgically corrected during infancy, was confirmed through clinical and radiological investigation. Additional musculoskeletal complications, including scoliosis and muscle deformity, were also identified. Interventions: The treatment plan addressed both SLOS and cleft palate. A prosthodontic appliance was prepared to assist with palatal function and speech therapy. Comprehensive care for SLOS included genetic counselling, nutrition management, and targeted physical therapy. The patient was also referred to an orthodontist, oral surgeon and a speech-language therapist further intervention. Conclusion: This case emphasizes the importance of early diagnosis and intervention in congenital disorders. It advocates for proactive, multidisciplinary care from infancy to enhance the quality of life for individuals with complex syndromes, underscoring the need for ongoing support and resources

Spatial and temporal expression analysis of BMP signal modifiers, Smoc1 and Smoc2, from postnatal to adult developmental stages in the mouse testis

Smoc1 and Smoc2, members of the SPARC family of genes, encode signaling molecules downstream of growth factors such as the TGF-β, FGF, and PDGF families. Smoc1 has been implicated in playing a crucial role in microphthalmia with limb anomalies in humans and mice, while Smoc2 deficiency causes dental developmental defects. Although developmental cytokines/growth factors including TGF-β superfamily have been shown to play critical roles in postnatal spermatogenesis, there are no reports analyzing the spatial and temporal expression of Smoc1 and Smoc2 in the postnatal testis. In this study, we investigated the mRNA and protein expression of Smoc1 and Smoc2 in neonatal, juvenile, and adult mouse testes by RNA in situ hybridization, immunofluorescence, and single-cell RNA-seq analysis. We show that Smoc1 and Smoc2 have distinct expression patterns in male germ cells: Smoc1 is more highly expressed than Smoc2 in the germline. In contrast, Smoc2 is highly expressed in testicular somatic cells from neonatal to juvenile stages. The Smoc2-expressing cells then switch from somatic cells to germ cells in adults. Thus, although SMOC1 and SMOC2 proteins are structurally very similar, their spatial and temporal expression patterns in the postnatal testis differ significantly, suggesting their distinct roles in reproduction.

Craniosynostosis in Siblings, an Extremely Rare Occurrence: A Case Report.

Craniosynostosis (CS) is the premature fusion of skull sutures, with all sutures except the metopic suture typically fusing in adulthood. Premature fusion constrains brain growth, leading to abnormal skull shape and potential neurocognitive or neurological issues, along with syndromic features in some cases. While CS is rare, its occurrence in siblings is exceptionally uncommon and holds significant academic importance. We report a case of CS in siblings: a 13-month-old boy and his five-and-a-half-year-old sister. Neither parent exhibits craniofacial dysmorphism or signs of increased intracranial pressure (ICP). The younger sibling presents with dolichocephaly and normal neurological, cognitive, and motor development, while the elder sibling exhibits proptosis, midface hypoplasia, and normal developmental milestones. Neither sibling displays limb or systemic anomalies. Imaging studies, including multislice plain CT brain with 3D skull reconstruction and MRI, revealed multiple suture closures. The younger sibling has complete sagittal suture closure with partial closure of other sutures, while the elder sibling shows multisutural CS. Ophthalmologic evaluations and developmental assessments excluded increased ICP and systemic issues. Most CS cases follow an autosomal dominant inheritance pattern, making this case particularly significant. CT with 3D skull reconstruction remains the diagnostic gold standard. Management aims to preserve cosmetic appearance and prevent complications from increased ICP. Treatment options range from conservative follow-up to surgical interventions, including endoscopic suturectomy, open craniotomy, and distraction osteogenesis, depending on the presence of neurocognitive issues or elevated ICP. Both siblings currently show normal neurological, cognitive, and motor development without increased ICP, emphasizing the need for ongoing monitoring to identify new developments or recurrence after treatment. Differential diagnoses, such as deformational plagiocephaly, must also be considered in such cases.

Prevalence, Mortality, and Associated Anomalies in Esophageal Atresia: A Retrospective Study of Finnish Population Data (2004-2017).

The aim of the study was to investigate the prevalence of esophageal atresia (EA), frequency of associated anomalies, and mortality from 2004 to 2017 in the Finnish population. We hypothesized the Spitz classification and the presence of other congenital malformations would predict mortality in patients with EA as well as assumed the survival to be high among patients with EA. This retrospective, population-based study was based on the registries maintained by THL Finnish Institute for Health and Welfare and Statistics Finland. The cases were identified and classified according to the World Health Organization's International Classification of Diseases and Health Related Problems (ICD) revisions 9 and 10 (ICD-9 and ICD-10) codes and accompanying written diagnoses. Associated anomalies were classified based on the EUROCAT criteria, and minor anomalies were excluded. All statistical tests were performed as a two-sided significance level set at p < 0.05. The chi-square or Fisher's exact test was utilized for categorical variables. The change in prevalence rates during the study period was evaluated with linear regression. In total, 337 cases with EA were identified including 295 (87.5%) live births, 17 (5.0%) stillbirths, and 25 (7.4%) terminations of pregnancy. The total prevalence for EA in Finland was 4.17/10,000 births with no significant change during the study period, p = 0.35. Neonatal mortality was 5% (n = 15) and 1-year survival was 91.5%. Mortality was associated with syndromic cases (p = 0.002). The Spitz classification predicted neonatal mortality better than cardiac anomalies alone (p < 0.001 and p = 0.6, respectively). Type C was the most common atresia type (65.9%) followed by type A (14.8%) and B (6.8%). The most common group of associated malformations were heart defects (35.0%) followed by other gastrointestinal tract malformations (15.3%) and limb anomalies (12.2%). Syndromic cases (12.2%) were associated with type A and B atresias (p = 0.001). VACTERL association was observed in 16.6% of the cases. The overall prevalence of EA remains stable and relatively high in Finland. Despite the high prevalence of co-occurring malformations, the overall survival rate is high. Spitz classification predicted neonatal survival well.

Elevated Telomeric Repeat-Containing RNA (TERRA) Levels Linked to Telomere Dysfunction and Telomerase Inactivity in Blood Cells of Children With Aplastic Anemia.

Background Aplastic anemia (AA) is characterized by pancytopenia and hypocellularity of the bone marrow. Certain inherited or genetic forms of AA have also been associated with telomere dysfunction. Here, we report the clinical manifestations of eleven AA patients aged between one and 12 years, along with the expression of a few candidate genes involved in the telomere length (TL) maintenance pathway. Methods The clinical manifestations were recorded for all the patients. The average telomere length of peripheral blood mononuclear cells (PBMC), the expression of telomerase subunits, telomere-associated proteins, and chromosome-specific telomeric repeat-containing RNA (TERRA) in whole blood cells of each patient was compared with an age-matched control group consisting of five clinically confirmed normal individuals. Results Out of 11 AA patients, four were found to have upper limb anomalies, and two showed short stature along with other defects. All the patients showed significantly shorter telomere length compared with the age-matched control group. The essential subunits of telomerase (hTERT and hTERC) were significantly low, and the shelterin protein is abnormally expressed in all patients implicating a compromised TL maintenance pathway. Notably, AA with combined androgen and prednisolone treatment showed a marked reduction of TERRA level than that of AA without androgen/prednisolone therapy. Conclusion Based on the findings and observations made, it appears that there might be an association between telomere dysfunction and elevated levels of TERRA in patients diagnosed with aplastic anemia who are 12 years of age or younger.

9342 Managing Osteoporosis In Patients With Phocomelia: Challenges And Strategies

Abstract Disclosure: M. Renzu: None. C. Hubers: None. V. Mehta: None. A.M. Qazi: None. A.M. Satei: None. D.K. Yerasuri: None. Introduction: Phocomelia, a rare congenital limb malformation, often results from disruptions in limb bud formation during embryonic stage, due to genetic mutations, teratogens, or environmental factors like thalidomide embryopathy. These disruptions pose unique challenges in bone health management, including an increased risk of osteoporosis.We present a case report of a 52-year-old patient with phocomelia who developed an early onset severe osteoporosis. This case stresses the need for specific measures and care to tackle bone health in individuals with congenital limb anomalies. Case Presentation: A 52-year-old white female with phocomelia, had absence of the left forearm and hand, as well as a transverse tibial deficiency with a prosthetic left lower leg since the age of 1. Osteoporosis was diagnosed after follow-up, with initial osteopenia noted at age 49. DEXA scan showed lumbar osteopenia, radial osteoporosis, and bilateral femoral neck osteopenia. FRAX score showed an 11.9% risk of osteoporotic fracture and 3.1% risk of a hip fracture.Risk factors to her osteoporosis included late menarche, early menopause due to hysterectomy, and a history of hormone replacement therapy without pregnancies. Also, chronic colitis and diarrhea caused malabsorption issues. Her left hip bone mineral density was disproportionately low due to chronic prosthesis use, necessitating close monitoring and treatment initiation with Denosumab, along with vitamin D3 and calcium supplementation.As of the latest follow-up, the patient is closely monitored, and improvement is noted in her condition. She has incorporated daily gym sessions into her routine, indicating proactive engagement in her well-being. Discussion: Managing osteoporosis in patients with phocomelia needs a personalized approach, considering the patient's unique anatomical challenges and the limitations of traditional osteoporosis management strategies. Bone tissue adapts its structure based on mechanical loading, with reduced loading in deformed limbs leading to increased resorption and elevated osteoporosis risk. Tailored treatment plans, including Denosumab, which is known as an effective pharmacological option for managing osteoporosis, complemented by dietary adjustments to enhance vitamin D and calcium intake. Physical therapy programs play a vital role in muscle strengthening and balance improvement, reducing fracture risk.Another challenge that patients with phocomelia face is barriers to accessing healthcare services, like limited specialized care providers, financial constraints, and transportation difficulties, leading to increased morbidity. Hence early screening and intervention are essential to prevent osteoporotic complications. Overall, a comprehensive approach to osteoporosis management in phocomelia patients is crucial for optimizing outcomes and enhancing quality of life. Presentation: 6/3/2024

Prevalence of Congenital Anomalies in Iran.

Annually, 3-8 million infants are born with congenital anomalies worldwide, ranging from 3% to 7% of births in different countries. This study aimed to investigate the nationwide epidemiological features of birth defects in Iran. This cross-sectional study was conducted in six major regions across Iran. The data sources were the maternity facilities affiliated with regional universities of medical sciences. All children were examined by obstetricians, pediatricians, or midwives at birth, and newborns were followed until discharge from the facility for health status, maturity, and congenital defects. A total of 138,643 births were registered in the maternity facilities across the study regions. Among these newborns, 3,458 cases were diagnosed with congenital anomalies, representing an overall prevalence rate of 249.4 per 10000 births (95% CI: 241.2-257.8). Genital organ anomalies exhibited the highest rates of defects in the country with 92.7 per 10000 births (95% CI: 86.4-98.9), followed by limb anomalies at 83.3 per 10000 births (95% CI: 77.4-89.3). The prevalence of respiratory system, chromosomal, and urinary tract anomalies was less than 10 per 10000 births. Until a national registry for congenital anomalies is established, this study provides essential data on the magnitude of the health problems caused by congenital anomalies in Iran. The findings would be vital for planning and evaluating antenatal screening for birth defects, particularly for high-risk groups and regions in the country.

Comparison Between Surgical Techniques for Correction of Congenital Syndactyly: A Systematic Review and Meta Analysis.

This review aimed to assess which surgical technique has better outcomes to correct one of the most common congenital anomalies of the upper limb: syndactyly. The following databases were used in the search: PubMed, Embase, Cochrane (CENTRAL), LILACS, SciELO, Scopus and Web of Science, on October 27, 2022. Studies that described a surgical technique for correcting syndactyly and evaluated surgical complications were included. Studies about noncongenital or foot syndactyly were excluded. The risk of bias was assessed using a specific method for case reports. For synthesis of results, the characteristics of the studies and techniques were demonstrated by a qualitative analysis. Meta-analysis models were applied for complications, functionality, and aesthetic. 73 studies were included, of which 70 were series or case reports, 27 studies did not use skin grafts and 7 studies used external fixators. To evaluate functional results, 42 studies used only the surgeon's opinion. Meta-analyses showed a higher incidence of scar defects when using skin grafts and of infection when using external fixators. There was no difference for web creep and readmission. Few studies evaluated results using the VSS scale, showing worse scar pigmentation when skin grafts were used, but there was no difference in other parameters (PROSPERO CRD42022368930).

Correlations of skeletal anomalies of the lower limbs and the mandibular ramus lengths

Correlations of skeletal anomalies of the lower limbs and the mandibular ramus lengths

A Unique Derivative Chromosome 4 with a Predominant 4p16.3 Microduplication Phenotype and a Literature Review

Introduction: Constitutional structural abnormalities affecting chromosome 4 result in variable distinct phenotypic traits including duplication 4p syndrome, deletion 4p or Wolf-Hirschhorn syndrome (WHS), deletion 4q and duplication 4q syndromes. Complex rearrangements involving both chromosome 4 arms are very rarely reported with different break points occurring within regions of 4p13-p16 and 4q32-35. They most commonly occur in familial cases due to parental pericentric inversion resulting in a recombinant chromosome 4 “rec(4).” The clinical picture is dependent on the size and type of copy number imbalance and the genes involved. Methods: We report on a female patient with delayed developmental milestones and lower limb anomalies, who carried a de novo unique type of complex rearrangement affecting both chromosome 4 arms, diagnosed by karyotype and fluorescence in situ hybridization analysis and chromosomal microarray (CMA). Results: The chromosome 4 rearrangement involved three copy number alterations, consisting of a terminal 1.17 Mb 4p16.3 deletion with a contiguous proximal 1.8 Mb 4p16.3 duplication, including the Wolf-Hirschhorn critical (WHSC) region, and an inverted 27 Mb terminal 4q32-35.2 duplication attached to terminal 4p. The patient’s predominant phenotype was consistent with 4p16.3 microduplication syndrome. The rearrangement occurred as a de novo abnormality, and thus it was designated as a derivative chromosome 4. To the best of our knowledge, this complex type of chromosome 4 rearrangement has not been reported so far. Conclusion: The present report adds to the scarce 4p16.3 microduplication syndrome reports and emphasizes the role of WHSC region in the syndromic phenotype. It also reveals the importance of CMA in detecting subtle copy number variations (CNVs) that could be dominantly reflected on the phenotype, which is very important in patients’ management and family counselling.

Facial dysmorphism and Limb abnormalities of Fetal Valproate Syndrome.

A neonate born to nonconsanguineous parents was evaluated for dysmorphic features. The neonate was born at term by normal vaginal delivery. The mother has had epilepsy for 12 years and has been on sodium valproate (700 mg/day) since conception and throughout pregnancy. Examination revealed facial dysmorphism, including triangular forehead, sparse arched eyebrows, telecanthus, flat nasal bridge, long thin upper vermilion border, smooth philtrum, and low-set ears. The limb anomalies observed were arachnodactyly, wrist and elbow contractures, clinodactyly, hypoplastic toenails, and overlapping toes. The other dysmorphisms noted were widely spaced nipples and hypospadias. Ultrasonogram (USG) cranium showed bilateral choroid plexus cysts, and USG abdomen revealed bilateral mild hydronephrosis. 2D-Echocardiography revealed a small patent ductus arteriosus (PDA). A diagnosis of fetal valproate syndrome (FVS) was considered, and other differentials, including fetal alcohol syndrome and genetic conditions, were ruled out by a clinical geneticist review. The index neonate is currently on multidisciplinary follow-up. The index neonate had common features of FVS as described in the literature, in addition to wrist and elbow contractures. Apart from the anomalies, there is a significant risk for neurocognitive delay and neurodevelopmental disorders. Postnatally, these babies need multidisciplinary care and neurodevelopmental follow-up. Valproate use for treating epilepsy in pregnant women and women of childbearing age may be restricted, and alternative choices of ASMs with better safety profiles should be preferred. Facial dysmorphism and limb anomalies in fetal valproate syndrome may occur irrespective of the dose of sodium valproate. Fetal valproate syndrome may present with wrist and elbow contractures.

Congenital malformations of the hand and fingers

Congenital anomalies of the upper limb are in Denmark estimated to have an incidence of around 20 in 10,000 live births. This covers a wide array of conditions summarised in this review. At the time of referral, the patient is thoroughly examined, and a treatment plan is discussed with the family. In some cases, no treatment is needed, in others there might be a need for surgery, night splinting, or an upper limb prosthesis. In case an underlying syndromatic cause is suspected, the patient is referred for paediatric evaluation at specialized centre.

Atypical Variants of Spinal Dysraphism: A Case Series

Abstract The aim of this study is to present and discuss atypical instances of spina bifida (SB) within a Nigerian paediatric cohort, highlighting their distinctive clinicoradiological features. Additionally, a brief literature review is provided to contextualise these congenital anomalies. This series comprises eight rare cases of SB managed in a Nigerian neurosurgical facility. Additionally, a brief literature review is provided to contextualise these congenital anomalies. This case series comprises eight rare cases of SB managed in a Nigerian neurosurgical facility. Amongst these, four cases exhibited segmental spinal dysgenesis (SSD; one thoracolumbar, one lumbar, and two sacral). Each of these cases demonstrated diverse associated musculoskeletal, cutaneous, and perineal anomalies, accompanied by varying degrees of neurological dysfunction. Other cases included lipomyelomeningocele (LMMC), human tail (HT), membranous meningocele, and myeloschisis (MSS). Autonomic dysfunction was a common feature in all of the cases, whilst two of the patients presented with congenital kyphotic spinal deformity. Lower limb anomalies varied, including congenital talipes equinovarus deformity, pes planus, congenital calcaneovagus deformity, rocker bottom feet, clinodactyly, and tetrapolydactyly. Remarkably, none of the patients exhibited clinical features indicative of hydrocephalus. SSD, LMMC, HT, membranous meningocele, and MSS represent atypical forms of SB in the Nigerian paediatric population. Early neuroimaging of patients with suspected spinal dysraphism is crucial, as it may reveal a spectrum of diverse vertebral anomalies associated with this neurological condition within the African population.

Epilepsy as a Novel Phenotype of BPTF-Related Disorders

BackgroundNeurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL. MethodsWe enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed. ResultsWe studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases. ConclusionsOur study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare.

Prenatal diagnosis of a severe form of frontonasal dysplasia with severe limb anomalies, hydrocephaly, a hypoplastic corpus callosum, and a ventricular septal defect using 3D ultrasound: a case report and literature review

BackgroundFrontonasal dysplasia (FND) is a rare congenital anomaly resulting from the underdevelopment of the frontonasal process, and it can be syndromic or nonsyndromic. The typical features of FND include a deformed nose and ocular hypertelorism, which are sometimes associated with cleft lip and/or palate. Only approximately 10 cases of prenatally diagnosed nonsyndromic FND have been reported in the past 30 years.Case presentationA 33-year-old woman (G2P1) was referred to our center at 20 gestational weeks for bilateral hydrocephaly. We detected typical features of FND, including severe hypertelorism, median nasal bifidity, a minor cleft lip, and multiple limb anomalies using three-dimensional (3D) ultrasound. A hypoplastic corpus callosum, unilateral microtia, and a ventricular septal defect were also detected. Genetic testing, including karyotype analysis, copy number variation (CNV) analysis, trio-whole exome sequencing (trio-WES), and trio-whole-gene sequencing (trio-WGS), was performed; however, we did not find any de novo gene variants in the fetus as compared to the parents. Postmortem examination confirmed the prenatal diagnosis of FND.ConclusionThe present case expands the wide phenotypic spectrum of prenatal FND patients. 3D ultrasound is a useful tool for detecting facial and limb deformities.

The sequence of acrania–exencephaly–anencephaly (AEAS)- An infrequent case report

Acrania–exencephaly–anencephaly sequence has an incidence of 3.6–5.4 for 10,000 live births and has been reported in literature. Exencephaly, described here is a defect of the neural tube which occurs due to the absence of closure of the neural fold. The main diagnostic ultrasound features include that are characterized by acrania, decreased size of cranial pole in comparison with the chest, irregular cranial surface, with increased amniotic fluid echogenicity due to the damaged brain tissue. Associated with amniotic band syndrome, Pentalogy of Cantrell, limb anomalies and ventral body wall defects. It is incompatible with life. Conducting programs training the budding neuro-sonographers about the knowledge in detection, diagnosis of NTD according to the Carnegie Classification is crucial to look forward in pathogenesis and application in the clinical scenario.

A de novo Mutation (p.Gln277X) of Cyclin D2 is Responsible for a Child with Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH), a type of overgrowth syndrome, is characterized by progressive megalencephaly, cortical brain malformations, and distal limb anomalies. Previous studies have revealed that the overactivity of the phosphatidylinositol 3-kinase-Protein kinase Bpathway and the increased cyclin D2 (CCND2) expression were the main factors contributing to this disease. Here, we present the case of a patient who exhibited megalencephaly, polymicrogyria, abnormal neuronal migration, and developmental delay. Serum tandem mass spectrometry and chromosome examination did not detect any metabolic abnormalities or copy number variants. However, whole-exome sequencing and Sanger sequencing revealed a de novo nonsense mutation (NM_001759.3: c.829C>T; p.Gln277X) in the CCND2 gene of the patient. Bioinformatics analysis predicted that this mutation may disrupt the structure and surface charge of the CCND2 protein. This disruption could potentially prevent polyubiquitination of CCND2, leading to its resistance against degradation. Consequently, this could drive cell division and growth by altering the activity of key cell cycle regulatory nodes, ultimately contributing to the development of MPPH. This study not only presents a new case of MPPH and expands the mutation spectrum of CCND2 but also enhances our understanding of the mechanisms connecting CCND2 with overgrowth syndromes.

Advancing the Clinical and Molecular Understanding of Cornelia de Lange Syndrome: A Multidisciplinary Pediatric Case Series and Review of the Literature.

Cornelia de Lange syndrome (CdLS) is a complex genetic disorder with distinct facial features, growth limitations, and limb anomalies. Its broad clinical spectrum presents significant challenges in pediatric diagnosis and management. Due to cohesin complex mutations, the disorder's variable presentation requires extensive research to refine care and improve outcomes. This article provides a case series review of pediatric CdLS patients alongside a comprehensive literature review, exploring clinical variability and the relationship between genotypic changes and phenotypic outcomes. It also discusses the evolution of diagnostic and therapeutic techniques, emphasizing innovations in genetic testing, including detecting mosaicism and novel genetic variations. The aim is to synthesize case studies with current research to advance our understanding of CdLS and the effectiveness of management strategies in pediatric healthcare. This work highlights the need for an integrated, evidence-based approach to diagnosis and treatment. It aims to fill existing research gaps and advocate for holistic care protocols and tailored treatment plans for CdLS patients, ultimately improving their quality of life.

Frequency of major congenital malformations in neonates born in three tertiary care hospitals of Pakistan.

Objective: To assess the frequency of major congenital anomalies in newborns delivered in three different hospitals of Pakistan. Study Design: Cross Sectional study. Setting: Department of Pediatrics Hameed Latif Teaching Hospital, Lahore, Ittefaq Hospital Lahore and HITEC-IMS Taxilla. Period: Jan 2023 to November 2023. Methods: 205 neonates who met the inclusion criteria were included in the study from labour room of Hameed Latif Teaching Hospital Lahore, Ittefaq Hospital Lahore and HITEC-IMS Taxilla. Informed consent was obtained from parents. Demographic variables (name of mother, gender, birthweight and gestational age at birth) were recorded. Then neonates were admitted in NICU and evaluated for presence of congenital malformations including cardiovascular system defects, limbs anomalies, genitourinary system, central nervous system and chromosomal anomalies. All data was entered in specially designed performa. Results: We found that overall gestational age was greater than 32 weeks with mean age of 37.190±2.00 weeks. Mean birth weight was 2.938±0.31 Kg. Frequency and %age of patients according to gender was 60% males and 40% females. Major congenital malformation was seen in 2.9% patients. Among infants with major congenital malformations, cardiovascular system defects were seen in 33.3% infants, limb anomalies 16.7%, genitourinary system 16.7% and central nervous system defects were 33.3%. Parents of 67.7% of cases were cousins. It was observed that only 32.3% of the mothers had taken the recommended daily dose of folic acid in antenatal period. Conclusion: Central nervous system and cardiovascular system defects were the most prominent anomalies detected. Prenatal diagnosis may be helpful in decreasing mortality by offering early termination.