RESUMO
PURPOSE: This study aimed to assess the real-world management of achondroplasia in Italy. METHODS: Two online surveys addressed to (1) parents/caregivers of individuals with achondroplasia and (2) Italian clinicians managing individuals with achondroplasia were conducted to assess real-world perspectives on achondroplasia management. Both surveys collected data on either patient or clinician demographics, details on diagnoses and referrals, disease complications, and views/experiences with limb lengthening surgery. RESULTS: In total, 42 parents/caregivers and 19 clinicians (from 18 hospitals) completed the surveys. According to parents/caregivers, achondroplasia diagnosis was most commonly made in the third trimester of gestation (55% of respondents), with a genetic test performed to confirm the diagnosis in all but one case. In contrast, the clinicians indicated that, while achondroplasia was typically suspected during the prenatal period (78%), diagnosis was more frequently confirmed postnatally (72%). Parents/caregivers reported that the greatest impact of achondroplasia-related complications occurred in their children between the ages of 2-5 years. The most significant complications were otitis, sleep apnoea, stenosis of the foramen magnum or pressure on the spinal cord, and hearing difficulties. Lengthening surgery had been presented as a treatment option to 92% of responding parents/caregivers, with 76% of clinicians viewing surgery favourably. Typically, clinicians' reasons for suggesting limb lengthening surgery were to improve patient quality of life, increase patient autonomy and self-acceptance, improve trunk-limb disproportion, short stature and walking, and ensure that all possible treatment options had been presented to the parents/caregivers. CONCLUSION: This survey provides insight into the real-world management of individuals with achondroplasia in Italy.
Assuntos
Acondroplasia , Qualidade de Vida , Criança , Humanos , Pré-Escolar , Cuidadores , Acondroplasia/diagnóstico , Acondroplasia/epidemiologia , Acondroplasia/terapia , Inquéritos e Questionários , PaisRESUMO
Drooling, or sialorrhea, is a common condition in patients with cerebral palsy, rare diseases, and neurodevelopmental disorders. The goal of this review was to identify the different properties of sialorrhea outcome measures in children. Four databases were analysed in search of sialorrhea measurement tools, and the review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. The COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist was used for quality appraisal of the outcome measures. The initial search yielded 891 articles, 430 of which were duplicates. Thus, 461 full-text articles were evaluated. Among these, 21 met the inclusion criteria, reporting 19 different outcome measures that encompassed both quantitative measures and parent/proxy questionnaires. Conclusions: Among the outcome measures found through this review, the 5-min Drooling Quotient can objectively discriminate sialorrhea frequency in patients with developmental disabilities. The Drooling Impact Scale can be used to evaluate changes after treatment. The modified drooling questionnaire can measure sialorrhea severity and its social acceptability. To date, the tests proposed in this review are the only tools displaying adequate measurement properties. The acquisition of new data about reliability, validity, and responsiveness of these tests will confirm our findings. What is Known: ⢠Although sialorrhea is a recognized problem in children with disabilities, especially those with cerebral palsy (CP), there is a lack of confidence among physicians in measuring sialorrhea. What is New: ⢠Few sialorrhea measures are available for clinicians that may guide decision-making and at the same time have strong evidence to provide confidence in the results. ⢠A combination of both quantitative measures and parent/proxy questionnaires might provide an adequate measurement of sialorrhea in children.
Assuntos
Paralisia Cerebral , Sialorreia , Paralisia Cerebral/complicações , Criança , Humanos , Avaliação de Resultados em Cuidados de Saúde , Reprodutibilidade dos Testes , Sialorreia/diagnóstico , Sialorreia/etiologia , Inquéritos e QuestionáriosRESUMO
Postzygotic mutations of the PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] gene constitutively activate the PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS) patients, causing congenital mosaic tissue overgrowth that even multiple surgeries cannot solve. mTOR inhibitors are empirically tested and given for compassionate use in these patients. PROS patients could be ideal candidates for enrolment in trials with PI3K/AKT pathway inhibitors, considering the "clean" cellular setting in which a unique driver, a PIK3CA mutation, is present. We aimed to assess the effects of blocking the upstream pathway of mTOR on PROS patient-derived cells by using ARQ 092, a potent, selective, allosteric, and experimental orally bioavailable and highly selective AKT-inhibitor with activity and long-term tolerability, currently under clinical development for treatment of cancer and Proteus syndrome. Cell samples (i.e., primary fibroblasts) were derived from cultured tissues obtained from six PROS patients [3 boys, 3 girls; aged 2 to 17 years] whose spectrum of PIK3A-related overgrowth included HHML [hemihyperplasia multiple lipomatosis; n = 1], CLOVES [congenital lipomatosis, overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies, scoliosis; n = 1], and MCAP [megalencephaly capillary malformation syndrome; n = 4]. We performed the following: (a) a deep sequencing assay of PI3K/AKT pathway genes in the six PROS patients' derived cells to identify the causative mutations and (b) a pathway analysis to assess the phosphorylation status of AKT [Ser473 and Thr308] and its downstream targets [pAKTS1 (Thr246), pRPS6 (Ser235/236), and pRPS6Kß1 (Ser371)]. The anti-proliferative effect of ARQ 092 was tested and compared to other PI3K/AKT/mTOR inhibitors [i.e., wortmannin, LY249002, and rapamycin] in the six PROS patient-derived cells. Using ARQ 092 to target AKT, a critical node connecting PI3K and mTOR pathways, we observed the following: (1) strong anti-proliferative activity [ARQ 092 at 0.5, 1, and 2.5 µM blunted phosphorylation of AKT and its downstream targets (in the presence or absence of serum) and inhibited proliferation after 72 h; rapamycin at 100 nM did not decrease AKT phosphorylation] and (2) less cytotoxicity as compared to rapamycin and wortmannin. We demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR. Clinical development of ARQ 092 in PROS patients is on going in these patients.
Assuntos
Aminopiridinas/administração & dosagem , Classe I de Fosfatidilinositol 3-Quinases/genética , Fibroblastos/efeitos dos fármacos , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/genética , Imidazóis/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Adolescente , Regulação Alostérica , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Mutação , Proteína Oncogênica v-akt/metabolismo , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacosRESUMO
Pallister-Killian syndrome (PKS) is a tissue limited mosaic disorder, characterized by variable degrees of neurodevelopmental delay and intellectual disability, typical craniofacial findings, skin pigmentation anomalies and multiple congenital malformations. The wide phenotypic spectrum of PKS in conjunction with the mosaic distribution of the i(12p) makes PKS an underdiagnosed disorder. Recognition of prenatal findings that should raise a suspicion of PKS is complicated by the fragmentation of data currently available in the literature and challenges in diagnosing a mosaic diagnosis on prenatal testing. Ultrasound anomalies, especially congenital diaphragmatic hernia, congenital heart defects, and rhizomelic limb shortening, have been related to PKS, but they are singularly not specific and are not present in all affected fetuses. We have combined prenatal data from 86 previously published reports and from our cohort of 114 PKS probands (retrospectively reviewed). Summarizing this data we have defined a prenatal growth profile and identified markers of perinatal outcome which collectively provide guidelines for early recognition of the distinctive prenatal profile and consideration of a diagnosis of PKS as well as for management and genetic counseling.
Assuntos
Transtornos Cromossômicos/diagnóstico , Diagnóstico Pré-Natal , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 12/genética , Feminino , Idade Gestacional , Humanos , Fenótipo , Gravidez , Diagnóstico Pré-Natal/métodos , Estudos Retrospectivos , Ultrassonografia Pré-NatalRESUMO
Cornelia de Lange syndrome (CdLS) and KBG syndrome are two distinct developmental pathologies sharing common features such as intellectual disability, psychomotor delay, and some craniofacial and limb abnormalities. Mutations in one of the five genes NIPBL, SMC1A, SMC3, HDAC8 or RAD21, were identified in at least 70% of the patients with CdLS. Consequently, additional causative genes, either unknown or responsible of partially merging entities, possibly account for the remaining 30% of the patients. In contrast, KBG has only been associated with mutations in ANKRD11. By exome sequencing we could identify heterozygous loss-of-function mutations in ANKRD11 in two patients with the clinical diagnosis of CdLS. Both patients show features reminiscent of CdLS such as characteristic facies as well as a small head circumference which is not described for KBG syndrome. Patient A, who carries the mutation in a mosaic state, is a 4-year-old girl with features reminiscent of CdLS. Patient B, a 15-year-old boy, shows a complex phenotype which resembled CdLS during infancy, but has developed to a more KBG overlapping phenotype during childhood. These findings point out the importance of screening ANKRD11 in young CdLS patients who were found to be negative for mutations in the five known CdLS genes.
Assuntos
Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Exoma , Estudos de Associação Genética , Fenótipo , Proteínas Repressoras/genética , Adolescente , Pré-Escolar , Fácies , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MasculinoRESUMO
We provide data on fetal growth pattern on the molecular subtypes of Beckwith-Wiedemann syndrome (BWS): IC1 gain of methylation (IC1-GoM), IC2 loss of methylation (IC2-LoM), 11p15.5 paternal uniparental disomy (UPD), and CDKN1C mutation. In this observational study, gestational ages and neonatal growth parameters of 247 BWS patients were compared by calculating gestational age-corrected standard deviation scores (SDS) and proportionality indexes to search for differences among IC1-GoM (n = 21), UPD (n = 87), IC2-LoM (n = 147), and CDKN1C mutation (n = 11) patients. In IC1-GoM subgroup, weight and length are higher than in other subgroups. Body proportionality indexes display the following pattern: highest in IC1-GoM patients, lowest in IC2-LoM/CDKN1C patients, intermediate in UPD ones. Prematurity was significantly more prevalent in the CDKN1C (64%) and IC2-LoM subgroups (37%). Fetal growth patterns are different in the four molecular subtypes of BWS and remarkably consistent with altered gene expression primed by the respective molecular mechanisms. IC1-GoM cases show extreme macrosomia and severe disproportion between weight and length excess. In IC2-LoM/CDKN1C patients, macrosomia is less common and associated with more proportionate weight/length ratios with excess of preterm birth. UPD patients show growth patterns closer to those of IC2-LoM, but manifest a body mass disproportion rather similar to that seen in IC1-GoM cases.
Assuntos
Síndrome de Beckwith-Wiedemann/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Metilação de DNA , Desenvolvimento Fetal/genética , Impressão Genômica , Dissomia Uniparental , Antropometria , Síndrome de Beckwith-Wiedemann/classificação , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/patologia , Cromossomos Humanos Par 11/química , Feto , Expressão Gênica , Genótipo , Idade Gestacional , Humanos , Recém-Nascido , Mutação , Fenótipo , Nascimento PrematuroRESUMO
Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.
Assuntos
Síndrome de Cornélia de Lange/genética , Face/anormalidades , Assimetria Facial/genética , Histona Desacetilases/genética , Mutação , Proteínas Repressoras/genética , Sequência de Aminoácidos , Sequência de Bases , Criança , Síndrome de Cornélia de Lange/patologia , Assimetria Facial/patologia , Fácies , Feminino , Aconselhamento Genético , Genótipo , Humanos , Masculino , Fenótipo , Fatores de Risco , Análise de Sequência de DNA/métodos , Homologia de Sequência de Aminoácidos , Índice de Gravidade de Doença , Inativação do Cromossomo XRESUMO
Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by postnatal growth deficiency, skeletal abnormalities, dysmorphic features and cognitive deficit. Mutations in two genes, CREBBP and EP300, encoding two homologous transcriptional co-activators, have been identified in Ë55% and Ë3-5% of affected individuals, respectively. To date, only eight EP300-mutated RSTS patients have been described and 12 additional mutations are reported in the database LOVD. In this study, EP300 analysis was performed on 33 CREBBP-negative RSTS patients leading to the identification of six unreported germline EP300 alterations comprising one deletion and five point mutations. All six patients showed a convincing, albeit mild, RSTS phenotype with minor skeletal anomalies, slight cognitive impairment and few major malformations. Beyond the expansion of the RSTS-EP300-mutated cohort, this study indicates that EP300-related RSTS cases occur more frequently than previously thought (Ë8% vs 3-5%); furthermore, the characterization of novel EP300 mutations in RSTS patients will enhance the clinical practice and genotype-phenotype correlations.
Assuntos
Proteína de Ligação a CREB/genética , Proteína p300 Associada a E1A/genética , Síndrome de Rubinstein-Taybi/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação , Síndrome de Rubinstein-Taybi/fisiopatologia , Deleção de SequênciaRESUMO
The genetic basis of Rubinstein-Taybi syndrome (RSTS), a rare, sporadic, clinically heterogeneous disorder characterized by cognitive impairment and a wide spectrum of multiple congenital anomalies, is primarily due to private mutations in CREBBP (approximately 55% of cases) or EP300 (approximately 8% of cases). Herein, we report the clinical and the genetic data taken from a cohort of 46 RSTS patients, all carriers of CREBBP point mutations. Molecular analysis revealed 45 different gene alterations including 31 inactivating (21 frameshift and 10 nonsense), 10 missense and 4 splicing mutations. Bioinformatic tools and transcript analyses were used to predict the functional effects of missense and splicing alterations. Of the 45 mutations, 42 are unreported and 3 were described previously. Recurrent mutations maybe a key tool in addressing genotype-phenotype correlations in patients sharing the same defects (at the genomic or transcript level) and specific clinical signs, demonstrated here in two cases. The clinical data of our cohort evidenced frequent signs such as arched eyebrows, epicanthus, synophrys and/or frontal hypertrichosis and broad phalanges that, previously overlooked in RSTS diagnosis, now could be considered. Some suggested correlations between organ-specific anomalies and affected CREB-binding protein domains broaden the RSTS clinical spectrum and perhaps will enhance patient follow-up and clinical care.
Assuntos
Proteína de Ligação a CREB/genética , Fenótipo , Mutação Puntual , Síndrome de Rubinstein-Taybi/metabolismo , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Simulação por Computador , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Alinhamento de Sequência , Adulto JovemRESUMO
BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a congenital neurodevelopmental disorder defined by postnatal growth deficiency, characteristic skeletal abnormalities and mental retardation and caused by mutations in the genes encoding for the transcriptional co-activators with intrinsic lysine acetyltransferase (KAT) activity CBP and p300. Previous studies have shown that neuronal histone acetylation is reduced in mouse models of RSTS. METHODS: The authors identified different mutations at the CREBBP locus and generated lymphoblastoid cell lines derived from nine patients with RSTS carrying distinct CREBBP mutations that illustrate different grades of the clinical severity in the spectrum of the syndrome. They next assessed whether histone acetylation levels were altered in these cell lines. RESULTS: The comparison of CREBBP-mutated RSTS cell lines with cell lines derived from patients with an unrelated mental retardation syndrome or healthy controls revealed significant deficits in histone acetylation, affecting primarily histone H2B and histone H2A. The most severe defects were observed in the lines carrying the whole deletion of the CREBBP gene and the truncating mutation, both leading to a haploinsufficiency state. Interestingly, this deficit was rescued by treatment with an inhibitor of histone deacetylases (HDACi). CONCLUSIONS: The authors' results extend to humans the seminal observations in RSTS mouse models and point to histone acetylation defects, mainly involving H2B and H2A, as relevant molecular markers of the disease.
Assuntos
Proteína de Ligação a CREB/genética , Histonas/metabolismo , Leucócitos Mononucleares/metabolismo , Síndrome de Rubinstein-Taybi/patologia , Acetilação , Adolescente , Adulto , Sequência de Bases , Biomarcadores/metabolismo , Proteína de Ligação a CREB/metabolismo , Linhagem Celular Transformada , Criança , Pré-Escolar , Cromatina/metabolismo , Análise Mutacional de DNA , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Feminino , Expressão Gênica , Haploinsuficiência , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Mutação , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/metabolismoRESUMO
Cornelia de Lange syndrome (CdLS) is a rare, congenital syndrome characterized by growth retardation, dysmorphic face, mental retardation and limb reduction defects. Clinical manifestations of CdLS can be extremely variable. Mutations in NIPBL, SMC1A and SMC3 genes, encoding for a regulator and two subunits of the cohesin complex, respectively, are found in 60-65% of CdLS patients. We report on a male with CdLS who is mosaic for the c.2827delA mutation in the NIPBL gene. Allele quantitation by pyrosequencing showed the presence of the mutation in about 10% and 33% of DNA samples from peripheral blood and buccal smears, respectively. The patient shows a complex phenotype: growth and psychomotor retardation are characteristic of the severe forms of CdLS, while the absence of severe limb reduction defects and major malformations are typical of the mild phenotype. He also has depigmentation areas following Blashko lines, an unusual finding in CdLS, which has been associated with mosaicism in other genetic conditions. This case represents the first evidence of somatic mosaicism in CdLS and explains the mild phenotype in the patient as compared to that predicted by a truncating mutation. Besides confirming the clinical and genetic heterogeneity of CdLS, this case also raises the likely underestimated mutation rate of known genes and points to the complexity of addressing genotype-phenotype correlations.
Assuntos
Síndrome de Cornélia de Lange/genética , Mosaicismo , Síndrome de Cornélia de Lange/diagnóstico , Genótipo , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , FenótipoRESUMO
Since the first description of Kabuki syndrome (KS) in 1981, over 350 cases from a variety of countries have been reported. Even though otolaryngological manifestations are common in KS, only a limited number of the reports provide audiological and vestibular data. The aim of the present study was to investigate the vestibular function and describe the audiological findings in KS. The present study reports no audiological and vestibular features in a group of 10 KS patients (7 males, 3 females), with chronological age ranging from 10 to 25 years (mean age = 14.5): a complete otoneurological and audiological work-up was performed for each patient and included where possible, the measurement of vestibular evoked potentials, caloric tests and static posturography. Hearing loss was found in 65% showing a mix or a conductive impairment; moreover the vestibular function was normal in 95% of the examined ears. In conclusion, audiological and vestibular examination should be considered when evaluating KS subjects.
Assuntos
Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Testes Calóricos , Criança , Potenciais Evocados Auditivos , Face/anormalidades , Feminino , Perda Auditiva , Humanos , Masculino , Síndrome , Doenças Vestibulares/diagnóstico , Testes de Função Vestibular , Adulto JovemRESUMO
Cornelia de Lange syndrome (CdLS) is a rare, multiple congenital anomaly/mental retardation syndrome characterized by varied clinical signs including facial dysmorphism, pre- and post-natal growth defects, small hands and malformations of the upper limbs. Established genetic causes include mutations in the NIPBL (50-60%), SMC1L1 and SMC3 (5%) genes. To detect chromosomal rearrangements pointing to novel positional candidate CdLS genes, we used array-CGH to analyze a subgroup of 24 CdLS patients negative for mutations in the NIPBL and SMC1L1 genes. We identified three carriers of DNA copy number alterations, including a de novo 15q26.2-qter 8-Mb deletion, and two inherited 13q14.2-q14.3 1-Mb deletion and 13q21.32-q21.33 1.5-Mb duplication, not reported among copy number variants. The clinical presentation of all three patients matched the diagnostic criteria for CdLS, and the phenotype of the patient with the 15qter deletion is compared to that of both CdLS and 15qter microdeletion patients.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/genética , Genoma Humano/genética , Proteínas/genética , Deleção Cromossômica , Hibridização Genômica Comparativa , Feminino , Humanos , Masculino , MutaçãoRESUMO
The aim of the study was to assess various aspects of visual and visuoperceptual function in patients with Noonan syndrome (NS) or LEOPARD syndrome (LS) with mutations affecting the PTPN11, SOS1 and RAF1 genes. Twenty-four patients were assessed with a battery of tests assessing visual function including ophthalmological and orthoptic evaluation and age appropriate behavioural visual tests, including measures of crowding acuity (Cambridge crowding cards), and stereopsis (TNO test). Twenty-one subjects were also assessed with the visuo-motor integration (VMI) test. Twenty of the 24 patients (83%) had abnormalities of visual function on at least one of the tests used to assess visual function or on ophthalmological examination, and 7 of 21 (33%) also had abnormalities on VMI. Ocular movements and stereopsis were most frequently abnormal (50% and 79%, respectively). Our results suggest that visual and visuoperceptual abilities are commonly impaired in patients with Noonan and LEOPARD syndrome and they are probably related to a multifactorial etiology.
Assuntos
Síndrome LEOPARD/diagnóstico , Síndrome de Noonan/diagnóstico , Transtornos da Percepção/diagnóstico , Transtornos da Visão/diagnóstico , Percepção Visual , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Percepção de Profundidade/genética , Feminino , Genótipo , Humanos , Síndrome LEOPARD/genética , Masculino , Síndrome de Noonan/genética , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/genética , Transtornos da Percepção/genética , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas c-raf/genética , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/genética , Proteína SOS1/genética , Transtornos da Visão/genética , Testes Visuais , Acuidade Visual/genética , Adulto JovemRESUMO
The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.
Assuntos
Síndrome de Beckwith-Wiedemann/genética , Cromossomos Humanos Par 15/genética , Metilação de DNA , Impressão Genômica , Síndrome de Silver-Russell/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Proteínas Reguladoras de Apoptose , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Fatores de Transcrição Kruppel-Like/química , Fatores de Transcrição Kruppel-Like/genética , Masculino , Mutação de Sentido Incorreto , Adulto JovemRESUMO
BACKGROUND: Living with a disabled child has profound effects on the entire family. With a prevalence of developmental disabilities around 2,5 %, there is a considerable need to promote improvements in the health care system. Little is known about changes and adaptations in the lives of affected families and this paucity of information hinders the improvement of services. This study sought to explore the needs and changes in the everyday life of families with children suffering from rare diseases of varying severity, with and without mental disability. The aim was to measure the socio-demographic characteristics, health care problems and living conditions of a large cohort of families with an affected member. METHODS: A sample of 154 families was recruited between September 2011 and April 2013 to respond to a 136 item questionnaire that explored different areas of concern (diagnosis and follow-up of clinical specialists, relationship with pediatrician, rehabilitation, school, work, institutional and/or private support, child care needs and family relationships). RESULTS: All parents answered the questionnaire. They were satisfied with the services provided in particular for diagnosis and follow-up, relationships with the family pediatrician, rehabilitation services and school, regardless of the severity of condition, presence of intellectual disability (ID) or absence of diagnosis. Negative scores were reported for institutional and/or private support and family relationships in severe conditions. CONCLUSIONS: The Health Care System should maintain a family-centered care and a multi-agency working, improving quality of life of families with disabled child to allow adaptation. At present these services are uncoordinated and financial support is poor, resulting in a heavy burden for these families.
Assuntos
Adaptação Psicológica , Deficiências do Desenvolvimento , Crianças com Deficiência , Saúde da Família , Doenças Raras , Atividades Cotidianas , Criança , Feminino , Necessidades e Demandas de Serviços de Saúde , Humanos , Itália , Estilo de Vida , Masculino , Pais/psicologia , Qualidade de Vida , Apoio Social , Inquéritos e QuestionáriosRESUMO
Germline mutations in genes coding for molecules involved in the RAS/RAF/MEK/ERK pathway are the hallmarks of a newly classified family of autosomal dominant syndromes termed RASopathies. Myeloproliferative disorders (MPDs), in particular, juvenile myelomonocytic leukemia, can lead to potentially severe complications in children with Noonan syndrome (NS). We studied 27 children with NS or other RASopathies and 35 age-matched children as control subjects. Peripheral blood (PB) cells from these patients were studied for in vitro colony-forming units (CFUs) activity, as well as for intracellular phosphosignaling. Higher spontaneous growth of both burst-forming units-erythroid (BFU-E) and CFU-granulocyte/macrophage (CFU-GM) colonies from RAS-mutated patients were observed as compared with control subjects. We also observed a significantly higher amount of GM-colony-stimulating factor-induced p-ERK in children with RASopathies. Our findings demonstrate for the first time that PB cells isolated from children suffering from NS or other RASopathies without MPD display enhanced BFU-E and CFU-GM colony formation in vitro. The biological significance of these findings clearly awaits further studies. Collectively, our data provide a basis for further investigating of only partially characterized hematological alterations present in children suffering from RASopathies, and may provide new markers for progression toward malignant MPD in these patients.
Assuntos
Leucócitos Mononucleares/fisiologia , Proteínas ras/metabolismo , Adolescente , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Humanos , Lactente , Síndrome LEOPARD , Masculino , Síndrome de Noonan , Transdução de SinaisRESUMO
Angelman syndrome is a neurobehavioral disorder caused by defects of imprinted gene(s) on chromosome 15q11-13. AS-specific DNA methylation is found in patients carrying 3-4 Mb deletions ( approximately 70%), paternal uniparental disomy (3-5%) or imprinting center mutations (2-9%), while normal methylation pattern with biparental inheritance characterizes the remaining approximately 20-25% AS patients (Stalker et al.,1998; Tsai et al.,1998). Mutations in the Ubiquitin protein ligase 3A gene (UBE3A) have been found in the latter group, but only preliminary figures are available on their frequencies. We selected a sample of 25 AS patients with a clinical diagnosis of AS and a normal methylation pattern in order to search for mutations of the UBE3A gene. Automated sequencing of exons 8, 9, 10, 11 and 12 performed on our 25 patients allowed us to identify three novel mutations: an 897insA in two unrelated familial cases, a 2544insA and an E167X in two sporadic cases. Mutation R482X previously reported in a sporadic patient was identified in a third familial case. Hum Mutat 15:387, 2000.
Assuntos
Síndrome de Angelman/enzimologia , Síndrome de Angelman/genética , Mutação da Fase de Leitura/genética , Ligases/genética , Mutação de Sentido Incorreto/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Itália , Masculino , Repetições de Microssatélites/genética , Ubiquitina-Proteína LigasesRESUMO
We report on two sets of monozygotic (MZ) twins with Williams syndrome (WS), following the 6 pairs already reported in the literature. We have confirmed monozygosity of both pairs of twins by DNA microsatellite analysis and the clinical diagnosis by fluorescence in situ hybridization using a WS-specific probe. Analysis of the concordance of different clinical signs between members of each pair of twins benefitted from a lengthy clinical follow-up, from 24 months to 7 years in one pair, and from the age of 15 years with reevaluation after 2 years in the other pair. Most clinical signs were concordant in the twins of each pair, with differences present at younger ages, mainly minor facial anomalies, being attenuated with time. Developmental delay was substantially concordant, but the degree differed slightly between twins in each pair. Inguinal hernia was present in a single twin in pair 1. Facial anomalies and other signs attributable to connective tissue abnormalities were also displayed by only one twin in both sets, suggesting that the WS genotype has only a predisposing role in the development of these signs.
Assuntos
Gêmeos Monozigóticos , Síndrome de Williams/genética , Adolescente , Criança , Pré-Escolar , DNA Satélite , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Fenótipo , Polimorfismo Genético , Síndrome de Williams/fisiopatologiaRESUMO
Kaufman oculocerebrofacial syndrome (KOS) is a rare autosomal recessive disorder characterized by severe mental retardation, microcephaly, long narrow face, ocular anomalies, and long thin hands and feet. To our knowledge only 8 cases have been reported so far, diagnosed at a mean age of 10 years. We report on a girl who was diagnosed at 15 years. Further phenotypic delineation is needed to improve diagnosis of this syndrome early in life.