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1.
Orphanet J Rare Dis ; 19(1): 111, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38462617

RESUMO

BACKGROUND: Cornelia de Lange (CdLS) is a rare genetic disorder that affects most body systems. Variants in multiple genes including NIPBL and SMC1A, can cause the syndrome. To date, literature on genotype-phenotype associations in individuals with CdLS is extremely limited, although studies suggest some differences in clinical phenotype severity across variants. This study aimed to examine and compare neurobehavioral differences and developmental variability across CdLS genes, specifically NIPBL and SMC1A, and identify genotype-phenotype correlations. PARTICIPANTS AND METHODS: This patient-reported outcomes study included accessing data from the Coordination of Rare Diseases registry at Sanford. Parents of a total of 26 children/adults with CdLS and a known variant in NIPBL (Mean age = 20.46 years, SD = 11.21) and 12 with a known variant in SMC1A (Mean age = 11.08 years, SD = 9.04) completed a series of questionnaires regarding their child's developmental history. This included attainment of common language and motor milestones, intervention history, and behavior functioning. Developmental history and reported behavior regulation difficulties were compared across variant groups. RESULTS: Overall, individuals with a pathogenic variant in NIPBL or SMC1A were similarly delayed across motor and language milestones with about 70% not using phrase speech and 30-50% not walking by 5 years of age. However, those with NIPBL variants showed more severity in behavioral phenotype, namely with more repetitive behaviors, tantrums, and withdrawn behaviors. In addition, these individuals were more likely than those with SMC1A variants to demonstrate self-injurious behaviors, and anxiety. Both groups yielded a similar proportion of participants who participated in speech and occupational therapy, however those with SMC1A variants were more likely to engage in physical therapy. Both clinical groups report low rate of communicative or assistive device use despite a large proportion of participants never mastering single word or sentence use. CONCLUSIONS: Study results are consistent with recent investigations highlighting more severe behavioral phenotype, particularly autistic features, anxiety, and behavior regulation challenges, among those with NIPBL variants albeit comparable developmental milestones. Both groups endorsed very elevated attention problems. Findings highlight importance of early interventions, including behavioral health services.


Assuntos
Proteínas de Ciclo Celular , Síndrome de Cornélia de Lange , Criança , Adulto , Humanos , Adulto Jovem , Proteínas de Ciclo Celular/genética , Síndrome de Cornélia de Lange/genética , Proteínas Cromossômicas não Histona/genética , Fenótipo , Estudos de Associação Genética
2.
Orphanet J Rare Dis ; 18(1): 104, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37143135

RESUMO

BACKGROUND: Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are debilitating conditions. Diagnosis is currently clinical in the absence of biomarkers, and criteria developed for adults are difficult to use in children and biologically immature adolescents. Generalized joint hypermobility (GJH) is a prerequisite for hEDS and generalized HSD. Current literature identifies a large proportion of children as hypermobile using a Beighton score ≥ 4 or 5/9, the cut off for GJH in adults. Other phenotypic features from the 2017 hEDS criteria can arise over time. Finally, many comorbidities described in hEDS/HSD are also seen in the general pediatric and adolescent population. Therefore, pediatric specific criteria are needed. The Paediatric Working Group of the International Consortium on EDS and HSD has developed a pediatric diagnostic framework presented here. The work was informed by a review of the published evidence. OBSERVATIONS: The framework has 4 components, GJH, skin and tissue abnormalities, musculoskeletal complications, and core comorbidities. A Beighton score of ≥ 6/9 best identifies children with GJH at 2 standard deviations above average, based on published general population data. Skin and soft tissue changes include soft skin, stretchy skin, atrophic scars, stretch marks, piezogenic papules, and recurrent hernias. Two symptomatic groups were agreed: musculoskeletal and systemic. Emerging comorbid relationships are discussed. The framework generates 8 subgroups, 4 pediatric GJH, and 4 pediatric generalized hypermobility spectrum disorders. hEDS is reserved for biologically mature adolescents who meet the 2017 criteria, which also covers even rarer types of Ehlers-Danlos syndrome at any age. CONCLUSIONS: This framework allows hypermobile children to be categorized into a group describing their phenotypic and symptomatic presentation. It clarifies the recommendation that comorbidities should be defined using their current internationally accepted frameworks. This provides a foundation for improving clinical care and research quality in this population.


Assuntos
Doenças do Tecido Conjuntivo , Síndrome de Ehlers-Danlos , Instabilidade Articular , Adulto , Adolescente , Humanos , Criança , Instabilidade Articular/diagnóstico , Síndrome de Ehlers-Danlos/diagnóstico , Pele
4.
J Child Health Care ; : 13674935221110081, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36128922

RESUMO

Hypermobile Ehlers-Danlos syndrome (hEDS) is a common disorder in children and adolescents that negatively impacts health-related quality of life (HRQOL). It can include chronic pain, fatigue, autonomic dysfunction, and mood problems. The objective of this study was to examine levels of agreement between children and parents in the setting of hEDS and HRQOL. Individuals with hEDS, ages 10-20 years, and their parents were recruited to complete a series of surveys. Instruments included pediatric quality of life generic and multidimensional fatigue scales, Functional Disability Index, Pain-Frequency-Severity-Duration scale, Brief Illness Perception Questionnaire, and Herth Hope Index. Agreement on each measure was evaluated using statistical calculations. Thirty-six parent-child dyads completed the surveys. There were no significant differences between the means of parent and child scores. There was moderate to strong agreement on all survey scores. However, the proportion of dyads with disagreement was relatively high for each individual score. Eighteen dyads disagreed on at least half of the surveys. Body mass index centile and child perception of cognitive fatigue most strongly predicted disagreement in total HRQOL score. Proxy-reporters for children and adolescents with hEDS may agree with their child on average. However, due to significant frequency of clinically important disagreement, information from both children and their parents should be sought whenever possible.

5.
J Child Neurol ; 37(5): 390-396, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35238682

RESUMO

Cornelia de Lange syndrome is a rare developmental malformation syndrome characterized by small stature, limb anomalies, distinctive facial features, developmental delays, and behavioral issues. The diagnosis of Cornelia de Lange syndrome is made clinically or on the basis of an identified variant in one of the genes associated with Cornelia de Lange syndrome. SMC1A variants are the cause of 5% of the cases of Cornelia de Lange syndrome. SMC1A is located on the X-chromosome and is thought to escape X-inactivation in some females. Patients with SMC1A variants are being increasingly identified through panel testing or exome sequencing without prior clinical suspicion of Cornelia de Lange syndrome. In general, intractable epilepsy is not considered a prominent feature of Cornelia de Lange syndrome, yet this is found in these patients with SMC1A variants. Here we report on a series of patients with SMC1A variants and intractable epilepsy. In contrast to patients with typical SMC1A-associated Cornelia de Lange syndrome, all of the identified patients were female, and when available, X-inactivation studies were highly skewed with truncating variants. We describe the medical involvement and physical appearance of the participants, compared to the diagnostic criteria used for classical Cornelia de Lange syndrome. We also report on the clinical characteristics of the epilepsy, including age of onset, types of seizures, electroencephalographic (EEG) findings, and response to various antiepileptic medications. These findings allow us to draw conclusions about how this population of patients with SMC1A variants fit into the spectrum of Cornelia de Lange syndrome and the broader spectrum of cohesinopathies and allow generalizations that may impact clinical care and, in particular, epilepsy management.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Síndrome de Cornélia de Lange , Epilepsia Resistente a Medicamentos , Epilepsia , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Epilepsia Resistente a Medicamentos/genética , Epilepsia/diagnóstico , Epilepsia/genética , Feminino , Humanos , Masculino , Fenótipo
6.
Am J Med Genet A ; 188(3): 1005-1014, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34877788

RESUMO

Cornelia de Lange syndrome (CdLS) is a spectrum disorder due to variants in genes of the cohesin protein complex. The following abstracts are from the Cornelia de Lange Syndrome Scientific and Educational Symposium held virtually in October 2020. Aspects of behavior, including autistic features, impulsivity, adaptive skills, executive function, and anxiety are described. Applied behavioral analysis is a promising approach for autism, and an N-acetylcysteine trial is proposed. Children below 6 years with CdLS have an increased number of and further travel to medical providers, with insurance type comprising a significant barrier. Speech, language, and feeding abilities fall significantly below expectations for age in CdLS. Augmentative alternative communication can yield potential barriers as well as interesting benefits. Developmentally, studies in animal models further elucidate the mechanisms and roles of cohesin: link with mediator transcriptional complex; facilitation of enhancer-promoter communication; regulation of gene expression; allocation of cells to germ layers; and repair of spontaneous DNA damage in placental cells. Genome and RNA sequencing can help identify the molecular cause in the 20% of individuals with suspected CdLS and negative testing. The phenotypes in individuals with variants in the SMC1A gene are distinct, and that with intractable seizures has been further evaluated. AMA CME credits provided by GBMC, Baltimore, MD. All studies approved by an ethics committee.

7.
J Autism Dev Disord ; 51(5): 1748-1758, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32809170

RESUMO

Cornelia de Lange syndrome (CdLS) is associated with repetitive and self-injurious behaviors (RBs, SIB). Evaluating children with CdLS, this study: (1) characterizes the spectrum of RBs; (2) characterizes the impact and severity of RBs including SIB; (3) describes how age and adaptive functioning relate to RBs including SIB. Fifty children (5-17 years) with CdLS were assessed with Children's Yale-Brown Obsessive Compulsive Scale Modified for PDD; Aberrant Behavior Checklist (ABC); Vineland Adaptive Behaviors Scales (VABS). All children had ≥ 1 type of RB; 44% had some form of SIB. 64% spent > 1 h/day displaying RBs. Lower VABS adaptive functioning was associated with higher stereotypy and SIB scores (ABC). In children with CdLS, RBs including SIB are common, impactful, and associated with lower adaptive functioning.


Assuntos
Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/psicologia , Comportamento Autodestrutivo/diagnóstico , Comportamento Autodestrutivo/psicologia , Comportamento Estereotipado , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Síndrome de Cornélia de Lange/complicações , Feminino , Humanos , Masculino , Comportamento Autodestrutivo/complicações , Comportamento Estereotipado/fisiologia
8.
Mol Genet Metab Rep ; 24: 100613, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32514400

RESUMO

Biallelic pathogenic variants in mitochondrial aminoacyl-tRNA synthetase (mt-aaRS) PARS2 are associated with mitochondrial cytopathy. Here, we report the tenth case of an individual with biallelic PARS2 pathogenic variants, detected by exome sequencing (ES), and a literature review of ten cases of PARS2 mutations. Our patient displayed symptoms and clinical and laboratory findings similar to those reported previously with normal lactate levels. These symptoms included seizure disorder (which was managed with antiepileptics), developmental delay, and progressive cardiomyopathy which manifested at 19 years of age. The patient received a vitamin regimen including antioxidants as part of his treatment regimen. While further studies are required to conclusively establish the beneficial role of vitamin and cofactor administration on the mitochondria in PARS2-associated mitochondrial disease, these factors may have delayed the onset of cardiomyopathy.

9.
Am J Med Genet A ; 179(6): 1080-1090, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30874362

RESUMO

Cornelia de Lange Syndrome (CdLS), due to mutations in genes of the cohesin protein complex, is described as a disorder of transcriptional regulation. Phenotypes in this expanding field include short stature, microcephaly, intellectual disability, variable facial features and organ involvement, resulting in overlapping presentations, including established syndromes and newly described conditions. Individuals with all forms of CdLS have multifaceted complications, including neurodevelopmental, feeding, craniofacial, and communication. Coping mechanisms and management of challenging behaviors in CdLS, disruption of normal behaviors, and how behavior molds the life of the individual within the family is now better understood. Some psychotropic medications are known to be effective for behavior. Other medications, for example, Indomethacin, are being investigated for effects on gene expression, fetal brain tissue, brain morphology and function in Drosophila, mice, and human fibroblasts containing CdLS-related mutations. Developmental studies have clarified the origin of cardiac defects and role of placenta in CdLS. Chromosome architecture and cohesin complex structure are elucidated, leading to a better understanding of regulatory aspects and controls. As examples, when mutations are present, the formation of loop domains by cohesin, facilitating enhancer-promotor interactions, can be eliminated, and embryologically, the nuclear structure of zygotes is disrupted. Several important genes are now known to interact with cohesin, including Brca2. The following abstracts are from the 8th Cornelia de Lange Syndrome Scientific and Educational Symposium, held in June 2018, Minneapolis, MN, before the CdLS Foundation National Meeting, AMA CME credits provided by GBMC, Baltimore, MD. All studies have been approved by an ethics committee.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Estudos de Associação Genética/métodos , Humanos , Coesinas
10.
Am J Med Genet A ; 179(4): 561-569, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30703284

RESUMO

Hypermobile Ehlers-Danlos syndrome (hEDS) is a hereditary disorder of connective tissue, often presenting with complex symptoms can include chronic pain, fatigue, and dysautonomia. Factors influencing functional disability in the pediatric hEDS population are incompletely studied. This study's aims were to assess factors that affect quality of life in children and adolescents with hEDS. Individuals with hEDS between the ages 12-20 years and matched parents were recruited through retrospective chart review at two genetics clinics. Participants completed a questionnaire that included the Pediatric Quality of Life Inventory (PedsQL™), PedsQL Multidimentional Fatigue Scale, Functional Disability Inventory, Pain-Frequency-Severity-Duration Scale, the Brief Illness Perception Questionnaire, measures of anxiety and depression, and helpful interventions. Survey responses were completed for 47 children and adolescents with hEDS/hypermobility spectrum disorder (81% female, mean age 16 years), some by the affected individual, some by their parent, and some by both. Clinical data derived from chart review were compared statistically to survey responses. All outcomes correlated moderately to strongly with each other. Using multiple regression, general fatigue and pain scores were the best predictors of the PedsQL total score. Additionally, presence of any psychiatric diagnosis was correlated with a lower PedsQL score. Current management guidelines recommend early intervention to prevent disability from deconditioning; these results may help identify target interventions in this vulnerable population.


Assuntos
Síndrome de Ehlers-Danlos/patologia , Instabilidade Articular/patologia , Qualidade de Vida , Adolescente , Adulto , Criança , Síndrome de Ehlers-Danlos/genética , Feminino , Humanos , Instabilidade Articular/genética , Masculino , Estudos Retrospectivos , Inquéritos e Questionários , Adulto Jovem
11.
Am J Med Genet A ; 176(9): 1858-1864, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30178919

RESUMO

The objective of this study was to explore the factors contributing to quality of life in pediatric patients with non-vascular Ehlers-Danlos syndromes (EDS). Data were analyzed on 41 children with a diagnosis of non-vascular EDS from the de-identified data available from the National Institute on Aging (NIA) study of heritable disorders of connective tissue. Children under age 19 years were seen as part of a long-term evaluation project from 2003 to 2013 on a larger natural history of patients with heritable disorders of connective tissue. Data collected included medical history, physical examination findings, diagnostic study results, and responses on validated questionnaires. We reviewed a sub-cohort of children with a diagnosis of non-vascular EDS and explored pain severity and interference via the Brief Pain Inventory, and sleep quality via the Pittsburgh Sleep Quality Index. Pain severity had a strong correlation with pain interference, and both were similar to other disorders that include chronic pain reported in the literature. Sleep quality did not correlate with pain severity or interference, but all patients had poor sleep quality in comparison to historical controls. We conclude that pain and sleep are significant issues in the pediatric non-vascular EDS population, and future research may be directed toward these issues.


Assuntos
Síndrome de Ehlers-Danlos/epidemiologia , Medição da Dor , Qualidade de Vida , Sono , Adolescente , Criança , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/diagnóstico , Feminino , Humanos , Masculino , Inquéritos e Questionários
12.
Am J Hum Genet ; 103(3): 448-455, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30122539

RESUMO

Neurodevelopment is a transcriptionally orchestrated process. Cyclin K, a regulator of transcription encoded by CCNK, is thought to play a critical role in the RNA polymerase II-mediated activities. However, dysfunction of CCNK has not been linked to genetic disorders. In this study, we identified three unrelated individuals harboring de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region and one individual harboring a de novo nonsynonymous variant c.331A>G (p.Lys111Glu) in CCNK. These four individuals, though from different ethnic backgrounds, shared a common phenotype of developmental delay and intellectual disability (DD/ID), language defects, and distinctive facial dysmorphism including high hairline, hypertelorism, thin eyebrows, dysmorphic ears, broad nasal bridge and tip, and narrow jaw. Functional assay in zebrafish larvae showed that Ccnk knockdown resulted in defective brain development, small eyes, and curly spinal cord. These defects were partially rescued by wild-type mRNA coding CCNK but not the mRNA with the identified likely pathogenic variant c.331A>G, supporting a causal role of CCNK variants in neurodevelopmental disorders. Taken together, we reported a syndromic neurodevelopmental disorder with DD/ID and facial characteristics caused by CCNK variations, possibly through a mechanism of haploinsufficiency.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Ciclinas/genética , Deficiências do Desenvolvimento/genética , Atrofia Muscular/genética , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Haploinsuficiência/genética , Heterozigoto , Humanos , Hipertelorismo/genética , Deficiência Intelectual/genética , Masculino , Anormalidades Musculoesqueléticas/genética , Malformações do Sistema Nervoso/genética , Fenótipo , Síndrome , Peixe-Zebra
13.
Nat Rev Genet ; 19(10): 649-666, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29995837

RESUMO

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.


Assuntos
Síndrome de Cornélia de Lange , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Consenso , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Síndrome de Cornélia de Lange/fisiopatologia , Síndrome de Cornélia de Lange/terapia , Estudos de Associação Genética , Humanos
14.
Eur J Hum Genet ; 26(9): 1272-1281, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29904177

RESUMO

Au-Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. AKS has been associated with de novo loss-of-function variants in HNRNPK (heterogeneous ribonucleoprotein K), and to date, only four of these patients have been described in the literature. Recently, an additional patient with a missense variant in HNRNPK was also reported. These patients have striking facial dysmorphic features, including long palpebral fissures, ptosis, deeply grooved tongue, broad nose, and down-turned mouth. Patients frequently also have skeletal and connective tissue anomalies, craniosynostosis, congenital heart malformations, and renal anomalies. In this report, we describe six new patients and review the clinical information on all reported AKS patients, further delineating the phenotype of AKS. There are now a total of 9 patients with de novo loss-of-function variants in HNRNPK, one individual with a de novo missense variant in addition to 3 patients with de novo deletions of 9q21.32 that encompass HNRNPK. While there is considerable overlap between AKS and Kabuki syndrome (KS), these additional patients demonstrate that AKS does have a distinct facial gestalt and phenotype that can be differentiated from KS. This growing AKS patient cohort also informs an emerging approach to management and health surveillance for these patients.


Assuntos
Anormalidades Múltiplas/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Deficiência Intelectual/genética , Fenótipo , Anormalidades Múltiplas/patologia , Criança , Deleção de Genes , Humanos , Lactente , Deficiência Intelectual/patologia , Mutação com Perda de Função , Masculino , Mutação de Sentido Incorreto , Síndrome , Adulto Jovem
15.
Hum Mol Genet ; 27(17): 3002-3011, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860495

RESUMO

Cornelia de Lange syndrome (CdLS) is a rare disease characterized by cognitive impairment, multisystemic alterations and premature aging. Furthermore, CdLS cells display gene expression dysregulation and genomic instability. Here, we demonstrated that treatment with antioxidant drugs, such as ascorbic acid and riboceine, reduced the level of genomic instability and extended the in vitro lifespan of CdLS cell lines. We also found that antioxidant treatment partially rescued the phenotype of a zebrafish model of CdLS. Gene expression profiling showed that antioxidant drugs caused dysregulation of gene transcription; notably, a number of genes coding for the zinc finger (ZNF)-containing Krueppel-associated box (KRAB) protein domain (KRAB-ZNF) were found to be downregulated. Taken together, these data suggest that antioxidant drugs have the potential to ameliorate the developmental phenotype of CdLS.


Assuntos
Antioxidantes/farmacologia , Biomarcadores/análise , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Mutação , Estresse Oxidativo/efeitos dos fármacos , Animais , Síndrome de Cornélia de Lange/genética , Síndrome de Cornélia de Lange/patologia , Perfilação da Expressão Gênica , Instabilidade Genômica , Humanos , Técnicas In Vitro , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
16.
Am J Med Genet A ; 173(9): 2323-2334, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28748642

RESUMO

Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology. Clinical data and images from 125 individuals with NS were obtained from 20 countries with an average age of 8 years and female composition of 46%. Individuals were grouped into categories of African descent (African), Asian, Latin American, and additional/other. Across these different population groups, NS was phenotypically similar with only 2 of 21 clinical elements showing a statistically significant difference. The most common clinical characteristics found in all population groups included widely spaced eyes and low-set ears in 80% or greater of participants, short stature in more than 70%, and pulmonary stenosis in roughly half of study individuals. Using facial analysis technology, we compared 161 Caucasian, African, Asian, and Latin American individuals with NS with 161 gender and age matched controls and found that sensitivity was equal to or greater than 94% for all groups, and specificity was equal to or greater than 90%. In summary, we present consistent clinical findings from global populations with NS and additionally demonstrate how facial analysis technology can support clinicians in making accurate NS diagnoses. This work will assist in earlier detection and in increasing recognition of NS throughout the world.


Assuntos
Face/fisiopatologia , Genética Populacional , Síndrome de Noonan/genética , Povo Asiático , População Negra/genética , Criança , Feminino , Humanos , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Síndrome de Noonan/fisiopatologia , Transdução de Sinais , População Branca/genética , Proteínas ras/genética
17.
Am J Med Genet A ; 173(5): 1172-1185, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28190301

RESUMO

Cornelia de Lange Syndrome (CdLS) is due to mutations in the genes for the structural and regulatory proteins that make up the cohesin complex, and is considered a cohesinopathy disorder or, more recently, a transcriptomopathy. New phenotypes have been recognized in this expanding field. There are multiple clinical issues facing individuals with all forms of CdLS, particularly in the neurodevelopmental system, but also gastrointestinal, cardiac, and musculoskeletal. Aspects of developmental and cell biology have found common endpoints in the biology of the cohesin complex, with improved understanding of the mechanisms, easier diagnostic tests, and the possibility of potential therapeutics, all major clinical implications for the individual with CdLS. The following abstracts are the presentations from the 7th Cornelia de Lange Syndrome Scientific and Educational Symposium, June 22-23, 2016, in Orlando, FL, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting. In addition to the scientific and clinical discussions, there were talks related to practical aspects of behavior including autism, transitions, communication, access to medical care, and databases. At the end of the symposium, a panel was held, which included several parents, affected individuals and genetic counselors, and discussed the greatest challenges in life and how this information can assist in guiding future research. The Research Committee of the CdLS Foundation organizes this meeting, reviews, and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board and publications. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/genética , Síndrome de Cornélia de Lange/fisiopatologia , Síndrome de Cornélia de Lange/diagnóstico , Humanos , Fenótipo , Coesinas
18.
Int J Pediatr Otorhinolaryngol ; 87: 203-7, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27368472

RESUMO

OBJECTIVES: Patients with Cornelia de Lange Syndrome (CdLS) are reported to have conductive (CHL) and sensorineural hearing loss (SNHL), but there is little information pertaining to the progression of hearing loss over time. The goal of this study was to examine the prevalence of CHL and SNHL in adults and children with CdLS and look for changes in SNHL over time. METHODS: Retrospective chart review of patients with CdLS presenting to a CdLS clinic was conducted. Also, a written survey of clinical concerns was collected from additional patients/families seen in the clinic and through the Cornelia de Lange Foundation. RESULTS: Seventy-eight patients (50% female) were included in the chart review. Mean age was 16.8 ± 11.4 years (range-0.6-50 years) and mean age at diagnosis of hearing loss was 4.6 ± 10.6 years (n = 26). Five patients (6.4%) had severe to profound SNHL that improved with time, including 2 who had complete normalization of audiogram results. Thirty-five families/patients completed the clinical survey, and 45.5% of the families reported a noticeable improvement of hearing over time. CONCLUSIONS: Conductive hearing loss and SNHL are common in CdLS. More than 50% of the patients seen in an adult CdLS clinic reported improvement in hearing loss over time, and a subset of patients had an improvement in SNHL. In light of these findings, we recommend longitudinal evaluations of hearing loss in these patients with both auditory brainstem response and otoacoustic emissions testing if SNHL is identified.


Assuntos
Síndrome de Cornélia de Lange/fisiopatologia , Perda Auditiva Condutiva/fisiopatologia , Perda Auditiva Condutiva-Neurossensorial Mista/fisiopatologia , Perda Auditiva Neurossensorial/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Cornélia de Lange/complicações , Progressão da Doença , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Perda Auditiva Condutiva/etiologia , Perda Auditiva Condutiva-Neurossensorial Mista/etiologia , Perda Auditiva Neurossensorial/etiologia , Testes Auditivos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Emissões Otoacústicas Espontâneas , Prevalência , Recuperação de Função Fisiológica , Estudos Retrospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto Jovem
19.
Am J Med Genet C Semin Med Genet ; 172(2): 190-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27164360

RESUMO

Neurobehavioral and developmental issues with a broad range of deficits are prominent features of Cornelia de Lange syndrome (CdLS), a disorder due to disruption of the cohesin protein complex. The etiologic relationship of these clinical findings to anatomic abnormalities on neuro-imaging studies has not, however, been established. Anatomic abnormalities in the brain and central nervous system specific to CdLS have been observed, including changes in the white matter, brainstem, and cerebellum. We hypothesize that location and severity of brain abnormalities correlate with clinical phenotype in CdLS, as seen in other developmental disorders. In this study, we retrospectively evaluated brain MRI studies of 15 individuals with CdLS and compared these findings to behavior at the time of the scan. Behavior was assessed using the Aberrant Behavior Checklist (ABC), a validated behavioral assessment tool with several clinical features. Ten of fifteen (67%) of CdLS patients had abnormal findings on brain MRI, including cerebral atrophy, white matter changes, cerebellar hypoplasia, and enlarged ventricles. Other findings included pituitary tumors or cysts, Chiari I malformation and gliosis. Abnormal behavioral scores in more than one behavioral area were seen in all but one patient. All 5 of the 15 (33%) patients with normal structural MRI studies had abnormal ABC scores. All normal ABC scores were noted in only one patient and this was correlated with moderately abnormal MRI changes. Although our cohort is small, our results suggest that abnormal behaviors can exist in individuals with CdLS in the setting of relatively normal structural brain findings. © 2016 Wiley Periodicals, Inc.


Assuntos
Encéfalo/patologia , Síndrome de Cornélia de Lange/patologia , Imageamento por Ressonância Magnética , Transtornos Mentais/diagnóstico , Adolescente , Adulto , Análise do Comportamento Aplicada , Criança , Pré-Escolar , Síndrome de Cornélia de Lange/complicações , Feminino , Humanos , Masculino , Estudos Retrospectivos , Adulto Jovem
20.
Am J Med Genet C Semin Med Genet ; 172(2): 83-5, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27109572

RESUMO

Although Laird G. Jackson, M.D., has mentored many individuals, most in the field of Medical Genetics, he remains inspirational and true to his basic tenets. This invited comment describes how he shaped the professional course of one of his "mentees." © 2016 Wiley Periodicals, Inc.


Assuntos
Síndrome de Cornélia de Lange , Fundações/organização & administração , Genética Médica , Diretores Médicos/organização & administração , História do Século XX , Mentores
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