Síndrome de Cornelia de Lange y su relación con la erupción dentaria. Análisis caso clínico.

El Síndrome de Cornelia de Lange (SCDL), es una anomalía genética cuya prevalencia es de 1:62.000-1:45.000 de los nacimientos. Se atribuye principalmente a mutaciones en los genes NIPBL, SMC3 y SMC1A. Se caracteriza por presentar alteraciones físicas generales, alteración cognitiva y del lenguaje; y rasgos orofaciales como la sinofridia, hirsutismo, también existe maloclusión, retardo de la erupción, apiñamiento, anodoncia, malformación de las extremidades, retraso del desarrollo pre y postnatal y otras malformaciones congénitas. Objetivo: Analizar el caso de paciente con síndrome de Cornelia de Lange y su relación con algunos hallazgos reportados en la literatura especialmente la erupción dentaria. Se presenta paciente lactante femenina de 2 años y 5 meses, procedente de Valencia, con diagnóstico genético de Síndrome de Cornelia de Lange, plumbemia, y litiasis biliar, que acude a la consulta del Postgrado de Odontopediatría de la Universidad de Carabobo por presentar retardo en la erupción dentaria. Se realiza historia clínica, examen clínico general donde se observa retraso psicomotor, del lenguaje y características fenotípicas propias del síndrome. A la evaluación clínica intrabucal se observa rebordes gingivales con inserción normal de frenillos y ausencia de unidades dentarias (retardo de erupción). La erupción dentaria puede verse afectada en pacientes con diagnóstico de Síndrome de Cornelia de Lange, tanto en su cronología como en la secuencia de erupción.

Classical Cornelia de Lange syndrome in a neonate

Cornelia de Lange syndrome is a rare developmental disorder syndrome involving multiple systems characterized by facial dysmorphism limb deformities, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. The features of this disorder range from mild to severe. We present here a case of preterm newborn with Classical Cornelia de Lange syndrome with heterozygous mutation in NIBPL gene.

The development of early social cognitive skills in neurogenetic syndromes associated with autism: Cornelia de Lange, fragile X and Rubinstein–Taybi syndromes

Background Cornelia de Lange (CdLS), Fragile X (FXS) and Rubinstein–Taybi syndromes (RTS) evidence unique profiles of autistic characteristics. To delineate these profiles further, the development of early social cognitive abilities in children with CdLS, FXS and RTS was compared to that observed in typically developing (TD) and autistic (AUT) children. Methods Children with CdLS (N = 22), FXS (N = 19) and RTS (N = 18), completed the Early Social Cognition Scale (ESCogS). Extant data from AUT (N = 19) and TD (N = 86) children were used for comparison. Results Similar to AUT children, children with CdLS, FXS and RTS showed an overall delay in passing ESCogS tasks. Children with CdLS showed a similar degree of delay to AUT children and greater delay than children with FXS and RTS. The CdLS, FXS and RTS groups did not pass tasks in the same sequence observed in TD and AUT children. Children with CdLS (p = 0.04), FXS (p = 0.02) and RTS (p = 0.04) performed better on tasks requiring understanding simple intentions in others significantly more than tasks requiring joint attention skills. Conclusions An underlying mechanism other than general cognitive delay may be disrupting early social cognitive development in children with CdLS, FXS and RTS. Factors that may disrupt early social cognitive development within these syndromes are discussed.

Liposome-Encapsulated Cytarabine and Daunorubicin (CPX-351) Induces Remission in Newly Diagnosed Pediatric Secondary Myeloid Malignancies

Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare myeloid neoplasms in children/adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT) but there has been little therapeutic innovation for decades and outcomes remain poor. CPX-351, a fixed 5:1 molar ratio of liposomal cytarabine/daunorubicin, has shown favorable safety and efficacy in elderly individuals with sAML and children with relapsed de novo AML, which led the FDA to recently expand the label of CPX-351 to include pediatric patients with secondary AML, however, no data has been reported in this patient group. We report the outcomes of seven young patients with newly diagnosed sMDS/AML uniformly treated with CPX-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-ALL; one had predisposing genomic instability disorder (Cornelia de Lange syndrome); and one presented with MDS-related AML and multi-organ failure. The median age at diagnosis of myeloid malignancy was 17 (13-23) years. We identified somatic mutations and copy-number changes across 16 leukemia driver genes in six cases (including TP53 in two), abnormal karyotypes in six cases and rearrangements involving MECOM or NIM1K-TERT in two patients. Additional genomic studies identified pathogenic germline mutations in CHEK2 and SMC3 each in a single patient . Patients received 1-3 cycles of CPX-351 (100 units/m 2 on days 1, 3, and 5) resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding FLT3 inhibitor as individualized therapy in one patient. Six patients were alive and leukemia-free at 0.51-3.25 years after HCT. One patient died from disease progression before HCT. Concluding, CPX-351 is an effective and well-tolerated regimen for cytoreduction in pediatric secondary myeloid malignancies warranting further investigation Figure 1 Figure 1. Disclosures Triplett: Miltenyi: Other: Travel, meeting registration.

Cornelia de Lange Syndrome as Paradigm of Chromatinopathies

Chromatinopathies can be defined as a class of neurodevelopmental disorders caused by mutations affecting proteins responsible for chromatin remodeling and transcriptional regulation. The resulting dysregulation of gene expression favors the onset of a series of clinical features such as developmental delay, intellectual disability, facial dysmorphism, and behavioral disturbances. Cornelia de Lange syndrome (CdLS) is a prime example of a chromatinopathy. It is caused by mutations affecting subunits or regulators of the cohesin complex, a multisubunit protein complex involved in various molecular mechanisms such as sister chromatid cohesion, transcriptional regulation and formation of topologically associated domains. However, disease-causing variants in non-cohesin genes with overlapping functions have also been described in association with CdLS. Notably, the majority of these genes had been previously found responsible for distinct neurodevelopmental disorders that also fall within the category of chromatinopathies and are frequently considered as differential diagnosis for CdLS. In this review, we provide a systematic overview of the current literature to summarize all mutations in non-cohesin genes identified in association with CdLS phenotypes and discuss about the interconnection of proteins belonging to the chromatinopathies network.

High rate of autonomic neuropathy in Cornelia de Lange Syndrome

Background Cornelia de Lange Syndrome (CdLS) is a rare congenital disorder characterized by typical facial features, growth failure, limb abnormalities, and gastroesophageal dysfunction that may be caused by mutations in several genes that disrupt gene regulation early in development. Symptoms in individuals with CdLS suggest that the peripheral nervous system (PNS) is involved, yet there is little direct evidence. Method Somatic nervous system was evaluated by conventional motor and sensory nerve conduction studies and autonomic nervous system by heart rate variability, sympathetic skin response and sudomotor testing. CdLS Clinical Score and genetic studies were also obtained. Results Sympathetic skin response and sudomotor test were pathological in 35% and 34% of the individuals with CdLS, respectively. Nevertheless, normal values in large fiber nerve function studies. Conclusions Autonomic nervous system (ANS) dysfunction is found in many individuals with Cornelia de Lange Syndrome, and could be related to premature aging.

CPX-351 Induces Remission in Newly Diagnosed Pediatric Secondary Myeloid Malignancies

Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children/adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT) but there has been no innovation in cytoreductive regimens. CPX-351, a fixed 5:1 molar ratio of liposomal cytarabine/daunorubicin, has shown favorable safety and efficacy in elderly individuals with sAML and children with relapsed de novo AML. We report the outcomes of seven young patients (six with newly diagnosed sMDS/AML and one with primary MDS/AML) uniformly treated with CPX-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-ALL; one had predisposing genomic instability disorder (Cornelia de Lange); and one MDS-related AML and multi-organ failure. The median age at diagnosis of myeloid malignancy was 17 (13-23) years. Patients received 1-3 cycles of CPX-351 (cytarabine 100mg/m2 plus daunorubicin 44mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding FLT3 inhibitor as individualized therapy in one patient. Six patients were alive and leukemia-free at 0.5-3.3 years after HCT. One patient died from disease progression before HCT. Concluding, CPX-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML warranting prospective studies.