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.

Thanks to a long-read sequencing (LRS) approach, in this study, we have reported a molecularly solved case of a proband with a clinical diagnosis of Cornelia de Lange syndrome (CDLS), which is a multisystemic disorder whose causative molecular defects involve cohesin complex genes, with NIPBL located at 5p13.2 accounting for approximately 50%-60% of CDLS cases. The first-tier tests revealed an abnormal karyotype 46,XY,t(5;15)(p13;q25)dn and a preserved NIPBL sequencing. Copy number variants (CNVs) at the translocation breakpoints, in disease genes, or in probably pathogenic loci were excluded by a-CGH analysis. Through fluorescence in situ hybridization (FISH) analysis on derivative chromosome 5, the breakpoint was relocated 3 Mb far from NIPBL 5\'UTR, which seemed fully maintained as FISH-probe mapping to the gene showed no split signals. Moreover, tri-color FISH revealed an apparently balanced paracentric inversion including NIPBL on derivative 5. Based on the strong clinical suspicion, we evaluated the NIPBL transcript by RT-qPCR that revealed a normal amount of transcript till exon 22 and a halved amount of the transcript from exon 23 to 3\'UTR, indicating the expression of a truncated transcript probably leading to a defective protein. Despite RT-qPCR confirmed the patient\'s CDLS clinical diagnosis, the molecular mechanism underlying this event remained to be an unsolved challenge for years. The LRS approach with nanopore technologies was able to fill the gap in this complex scenario and highlighted a chromothripsis event marked out at 5p13.2 by 36 breaks clustered in a 7.3-Mb region. The NIPBL gene was disrupted by 16 breaks and the resulting fragments were relocated in different positions and orientations. LRS confirmed the previous findings, and it has been proven to be crucial to define the complex chromosomal rearrangement in this patient which escaped current diagnostic investigations. Its application in the clinical practice will contribute to solve the unsolved.

BACKGROUND: Cornelia de Lange syndrome is a rare genetic disease with otolaryngological involvement. The classic phenotype is characterized by distinctive facial features, intellectual disability, growth delay, hirsutism, and upper-limb reduction. Nasal polyposis was previously reported in association with chronic rhinosinusitis, however data about prevalence, diagnosis, treatment and prognosis are lacking for this cohort of patients, affected by rare disease.
METHODS: We describe the whole diagnostic and therapeutic workflow of nasal polyps in two pediatric patients with Cornelia de Lange, successfully diagnosed and treated by nasal endoscopy.
CONCLUSIONS: Our report confirm that nasal endoscopy is a safe and useful tool in the diagnosis, treatment and follow-up of nasal polyps, even in Cornelia de Lange syndrome pediatric patients. We want to increase the alert for the detection of nasal polyps in patients with Cornelia de Lange syndrome since pediatric age. We recommend endoscopy in all patients with Cornelia de Lange syndrome and symptoms of chronic nasal obstruction and/or OSAS. Multidisciplinary team and sedation service could be useful in the management of Cornelia de Lange syndrome patients with airway obstruction symptoms and sleep disturbance when severe intellectual disability, autism or psychiatric findings are present.

Cornelia de Lange syndrome (CdLS) is an autosomal dominant or X-linked genetic disease with significant genetic heterogeneity. Variants of the NIPBL gene are responsible for CdLS in 60% of patients. Herein, we report the case of a patient with CdLS showing distinctive facial features, microcephaly, developmental delay, and growth retardation. Whole exome sequencing was performed for the patient, and a novel de novo heterozygous synonymous variant was identified in the deep region of exon 40 in the NIPBL gene (NM_133433.4: c. 6819G > T, p. Gly2273 = ). The clinical significance of the variant was uncertain according to the ACMG/AMP guidelines; however, based on in silico analysis, it was predicted to alter mRNA splicing. To validate the prediction, a reverse transcriptase-polymerase chain reaction was conducted. The variant activated a cryptic splice donor, generating a short transcript of NIPBL. A loss of 137 bp at the 3\' end of NIPBL exon 40 was detected, which potentially altered the open reading frame by inserting multiple premature termination codons. Quantitative real-time PCR analysis showed that the ratio of the transcription level of the full-length transcript to that of the altered short transcript in the patient was 5:1, instead of 1:1. These findings may explain the relatively mild phenotype of the patient, regardless of the loss of function of the truncated protein due to a frameshift in the mRNA. To the best of our knowledge, this study is the first to report a synonymous variant in the deep exon regions of the NIPBL gene responsible for CdLS. The identified variant expands the mutational spectrum of the NIPBL gene. Furthermore, synonymous variations may be pathogenic, which should not be ignored in the clinical and genetic diagnosis of the disease.

Ultimate advances in genetic technologies have permitted the detection of transmitted cases of congenital diseases due to parental gonadosomatic mosaicism. Regarding Cornelia de Lange syndrome (CdLS), up to date, only a few cases are known to follow this inheritance pattern. However, the high prevalence of somatic mosaicism recently reported in this syndrome (∼13%), together with the disparity observed in tissue distribution of the causal variant, suggests that its prevalence in this disorder could be underestimated. Here, we report a new case of parental gonadosomatic mosaicism in SMC1A gene that causes inherited CdLS, in which the mother of the patient carries the causative variant in very low allele frequencies in buccal swab and blood. While the affected child presents with typical CdLS phenotype, his mother does not show any clinical manifestations. As regards SMC1A, the difficulty of clinical identification of carrier females has been already recognized, as well as the gender differences observed in CdLS expressivity when the causal variant is found in this gene. Currently, the use of DNA deep-sequencing techniques is highly recommended when it comes to molecular diagnosis of patients, as well as in co-segregation studies. These enable us to uncover gonadosomatic mosaic events in asymptomatic or oligosymptomatic parents that had been overlooked so far, which might have great implications regarding genetic counseling for recurrence risk.

The prone position can lead to anatomical compression of the thoracic cavity resulting in reduced cardiac output, especially in the context of chest wall deformities commonly present in patients with scoliosis. There are no protocols for using transesophageal echocardiography (TEE) to optimize prone positioning and for safe use of TEE during cases requiring neuromonitoring.
We present a case of a 23-yr-old male with Cornelia de Lange syndrome undergoing elective posterior spinal fusion for syndromic scoliosis who developed severe refractory hypotension and cardiac arrest in the prone position. After hemodynamic stabilization in the intensive care unit, the patient returned to the operating room on postoperative day 2 for completion of his spinal fusion. Transesophageal echocardiography determined the optimal position of longitudinal bolster placements associated with minimal left ventricular compression in the supine position. The patient was then proned and intraoperative hemodynamics during the second surgery remained stable. Owing to the special considerations of using TEE in the prone position with neuromonitoring, we describe technical aspects to consider to protect the equipment and patient.
Patients with compliant chest walls or thoracic deformities are at risk of hemodynamic instability in the prone position. Intraoperative TEE can be used in the supine patient prior to proning to determine optimal longitudinal bolster positioning to minimize cardiac compression. Transesophageal echocardiography used during spine surgery in the prone position with neuromonitoring and motor-evoked potentials requires special considerations for patient safety.
RéSUMé: OBJECTIF: La position ventrale peut entraîner une compression anatomique de la cavité thoracique provoquant une réduction du débit cardiaque, en particulier dans le contexte de déformations de la paroi thoracique, fréquentes chez les patients atteints de scoliose. Il n’existe aucun protocole guidant l’utilisation de l’échocardiographie transœsophagienne (ETO) pour optimiser le positionnement ventral et pour favoriser l’utilisation sécuritaire de l’ETO dans les cas nécessitant un neuro-monitorage. CARACTéRISTIQUES CLINIQUES: Nous présentons le cas d’un homme de 23 ans atteint d’un syndrome de Cornelia de Lange bénéficiant d’une fusion spinale postérieure non urgente pour traiter une scoliose syndromique; le patient a manifesté une hypotension réfractaire sévère et un arrêt cardiaque en position ventrale. Après stabilisation hémodynamique à l’unité de soins intensifs, le patient est retourné en salle d’opération au jour postopératoire 2 pour terminer sa fusion spinale. L’échocardiographie transœsophagienne a permis de déterminer la position optimale des traversins longitudinaux qui était associée à une compression ventriculaire gauche minimale en décubitus dorsal. Le patient a ensuite été positionné sur le ventre, et les valeurs hémodynamiques peropératoires sont restées stables au cours de la deuxième chirurgie. En raison des considérations particulières de l’utilisation de l’ETO en position ventrale avec neuro-monitorage, nous décrivons les aspects techniques à prendre en compte pour protéger l’équipement et le patient. CONCLUSION: Les patients présentant des parois thoraciques compliantes ou des déformations thoraciques sont à risque d’instabilité hémodynamique en position ventrale. L’ETO peropératoire peut être utilisée chez le patient en décubitus dorsal avant le positionnement ventral pour déterminer le positionnement optimal des traversins longitudinaux afin de minimiser la compression cardiaque. L’utilisation de l’échocardiographie transœsophagienne lors d’une chirurgie du rachis en position ventrale avec neuro-monitorage et potentiels évoqués moteurs nécessite des considérations particulières en ce qui a trait à la sécurité des patients.

Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient\'s phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS.

BACKGROUND: This case report describes a novel genotypic and phenotypic presentation of Alazami-Yuan syndrome, and contributes to the current knowledge on the condition.
METHODS: We report an 11-year-old boy with Alazami-Yuan syndrome. The main clinical manifestations were rapid development of puberty, typical facial features of Cornelia de Lange syndrome, and normal intelligence. Peripheral blood DNA samples obtained from the patient and his parents were sequenced using high-throughput whole-exosome sequencing, which was verified by Sanger sequencing. The results showed that there was a compound heterozygous mutation of c.1052delT and c.76A>T in the TATA-Box Binding Protein Associated Factor 6 (TAF6) gene. The mutation of c.1052delT was from his mother and the mutation of c.76A>T was from his father.
CONCLUSIONS: This study extends the mutation spectrum of the TAF6 gene, and provides a molecular basis for the etiological diagnosis of Alazami-Yuan syndrome and genetic consultation for the family.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a congenital multisystemic genetic disorder. The expected lifespan of children with this disorder has been prolonged in parallel with the advances in medicine in recent years. However, they still more frequently undergo cardiac surgery. There are some challenges for clinicians when faced with CdLS patients. We present the perioperative management of a child with CdLS undergoing open-heart surgery.
METHODS: Severe pulmonic and subpulmonic valvular stenosis, enlargement of the right side of the heart, mild tricuspid regurgitation, atrial septal defect, and patent ductus arteriosus were diagnosed in a 14-month-old boy with manifested cyanosis, developmental delay, and malnutrition. Attempted balloon valvuloplasty was unsuccessful due to a severe stenotic pulmonary valve, therefore it was decided to perform an open surgical repair. Following a successful and uncomplicated intraoperative course, the patient was extubated on postoperative day 5, and adrenalin and dopamine infusions were gradually decreased and stopped on postoperative days 6 and 10, respectively. Moderate laryngomalacia and suboptimal vocal cord movements were diagnosed, and tracheotomy and percutaneous endoscopic gastrostomy were performed under general anesthesia in the same session at postoperative day 32. The patient was discharged on postoperative day 85 after a challenging postoperative period with additional airway and nutritional problems.
CONCLUSIONS: This is the first report of the perioperative anesthetic and clinical management of a CdLS patient undergoing open-heart surgery.

Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder, and cases caused by variants in SMC3 are infrequent. This article describes a case of CdLS related to a pathogenic variant in SMC3 and performs a literature review.
We collected clinical data and biological samples from a 12-year-old boy with \"short stature for 11 years\". Gene variants in the proband were detected by whole-exome sequencing, and the variants in his parents were verified by Sanger sequencing. All SMC3-related CdLS patients from the PubMed and Web of Science databases were collected and summarized using the available data.
A pathogenic variant in SMC3 in the proband, c.1942A>G, was identified. Neither of his parents carried the same variant. Twenty-eight patients were diagnosed with CdLS with variants in SMC3, including the cases in this study and those reported in the literature, where half of the variant types were missense, followed by 32% (9/28) with a deletion and 11% (3/28) with a duplication. All patients showed symptoms of verbal development delay and intellectual disability to different degrees, and 90% patients had long eyelashes while 89% patients had arched eyebrows.
This study summarized different gene variants in SMC3 and the frequencies of the various clinical manifestations according to the reported literature. For CdLS caused by SMC3 variants, short stature and facial dysmorphic features are the two most important clinical clues. Definite diagnosis of this rare disease may be challenging clinically; thus, it is significant to use molecular diagnosis.