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1.
J Hum Genet ; 66(11): 1121-1126, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34031513

RESUMEN

Silver-Russell syndrome (SRS) is a congenital disorder characterized by prenatal and postnatal growth failure and craniofacial features. Hypomethylation of the H19/IGF2:IG-differential methylated region (H19LOM) is observed in 50% of SRS patients, and 15% of SRS patients with H19LOM had multilocus imprinting disturbance (MLID). Schimke immuno-osseous dysplasia (SIOD), characterized by spondyloepiphyseal dysplasia and nephropathy, is an autosomal recessive disorder caused by mutations in SMARCAL1 on chromosome 2. We report a patient with typical SRS-related features, spondyloepiphyseal dysplasia, and severe nephropathy. Molecular analyses showed H19LOM, paternal uniparental isodisomy of chromosome 2 (iUPD(2)pat), and a paternally inherited homozygous frameshift variant in SMARCAL1. Genome-wide methylation analysis showed MLID in this patient, although it showed no MLID in another patient with SIOD without SRS phenotype. These results suggest that iUPD(2)pat unmasked the recessive mutation in SMARCAL1 and that the SMARCAL1 gene mutation may have no direct effect on the patient's methylation defects.


Asunto(s)
Arteriosclerosis/genética , ADN Helicasas/genética , Metilación de ADN/genética , Síndrome Nefrótico/genética , Osteocondrodisplasias/genética , Enfermedades de Inmunodeficiencia Primaria/genética , Embolia Pulmonar/genética , Síndrome de Silver-Russell/genética , Arteriosclerosis/complicaciones , Arteriosclerosis/fisiopatología , Niño , Preescolar , Cromosomas Humanos Par 2/genética , Femenino , Genoma Humano/genética , Impresión Genómica/genética , Humanos , Recién Nacido , Masculino , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/fisiopatología , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/fisiopatología , Fenotipo , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Enfermedades de Inmunodeficiencia Primaria/fisiopatología , Embolia Pulmonar/complicaciones , Embolia Pulmonar/fisiopatología , Síndrome de Silver-Russell/complicaciones , Síndrome de Silver-Russell/fisiopatología , Disomía Uniparental/genética , Disomía Uniparental/fisiopatología
2.
Arch. argent. pediatr ; 118(3): e258-e264, jun. 2020. tab, ilus
Artículo en Inglés, Español | LILACS, BINACIS | ID: biblio-1116915

RESUMEN

El síndrome de Silver-Russell se caracteriza por retraso del crecimiento intrauterino asimétrico, con circunferencia craneal normal, barbilla pequeña y puntiaguda, que proporciona un aspecto de rostro triangular. Puede, además, presentar asimetría corporal, entre otros. Tiene una incidencia mundial estimada de 1 en 30 000-100 000 nacimientos, aunque este número es, probablemente, subestimado. En alrededor del 60 % de los casos, se puede identificar una causa molecular y la principal es la hipometilación del alelo paterno en la región de control de impresión 1 localizado en 11p15.5-p15.4. Realizar el diagnóstico de esta entidad, excluir los diagnósticos diferenciales y conocer las correlaciones (epi)genotipo-fenotipo son necesarios para realizar el adecuado seguimiento, brindar las opciones terapéuticas disponibles y el oportuno asesoramiento genético familiar. El objetivo del presente artículo es mostrar el estado actual del síndrome de Silver-Russell, un ejemplo de trastorno de impronta genómica.


Silver-Russell syndrome is characterized by asymmetrical intrauterine growth retardation, with normal head circumference and small, pointed chin, which results in a triangular face. It can also include body asymmetry, among other characteristics. Its global incidence is estimated at 1 in 30 000-100 000 births, even though this figure may be underestimated. In approximately 60 % of cases, a molecular cause can be identified, and the main one is hypomethylation of the paternal allele at the imprinting control region 1 located at 11p15.5-p15.4. It is necessary to make the diagnosis of this entity, exclude differential diagnoses, and know (epi)genotype-phenotype correlations in order to ensure an adequate follow-up, provide available therapeutic options, and offer a timely family genetic counseling. The objective of this article is to describe the current status of the Silver-Russell syndrome, a model of genomic imprinting disorder.


Asunto(s)
Humanos , Masculino , Femenino , Síndrome de Silver-Russell/fisiopatología , Fenotipo , Impresión Genómica , Diagnóstico Diferencial , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/terapia , Retardo del Crecimiento Fetal , Asesoramiento Genético , Genotipo
3.
Arch Dis Child ; 104(1): 76-82, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29954740

RESUMEN

OBJECTIVE: There is limited information on the psychosocial impact of growing up with Silver-Russell syndrome (SRS), characterised by slow growth in utero leading to short stature in adulthood. Such information could aid families in making difficult treatment decisions and guide management strategies for health professionals. We aimed to explore the lived experience of people with SRS across the lifespan. DESIGN/SETTING/PATIENTS: In-depth, semi-structured interviews were conducted between January 2015 and October 2016 with a sample of 15 adults (six women) with genetically confirmed SRS from the UK. Qualitative interviews were transcribed and coded to identify similarities and differences: codes were then grouped to form overarching themes. RESULTS: Four themes were identified from participant accounts: (1) appearance-related concerns extending beyond height; (2) strategies to deal with real and perceived threats; (3) women's experiences of pain, disability and feeling older than their years; and (4) feeling overlooked in romantic relationships. These themes show that other factors, beyond short stature, affect patient well-being and indicate a mismatch between patient need and healthcare provision. CONCLUSIONS: Challenges in SRS during childhood and adolescence were central to the psychosocial impact of SRS, and were not limited to height. These challenges, as well as symptoms such as pain and fatigue for women, have not previously been documented. To help individuals with SRS develop strategies to manage psychosocial issues, we recommend clinicians incorporate psychological services as an integral part of multidisciplinary teams managing individuals with SRS during childhood, adolescence and adulthood.


Asunto(s)
Adaptación Psicológica/fisiología , Estatura , Enanismo , Dolor , Síndrome de Silver-Russell , Adulto , Niño , Evaluación de la Discapacidad , Enanismo/etiología , Enanismo/fisiopatología , Enanismo/psicología , Fatiga/diagnóstico , Fatiga/etiología , Femenino , Humanos , Masculino , Evaluación de Necesidades , Dolor/diagnóstico , Dolor/etiología , Psicología , Factores Sexuales , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/epidemiología , Síndrome de Silver-Russell/fisiopatología , Síndrome de Silver-Russell/psicología , Reino Unido/epidemiología
4.
J Med Genet ; 55(7): 497-504, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29574422

RESUMEN

BACKGROUND: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance. METHODS: Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found. RESULTS: We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss. CONCLUSION: The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Síndrome de Beckwith-Wiedemann/genética , Desiminasas de la Arginina Proteica/genética , Síndrome de Silver-Russell/genética , Proteínas Reguladoras de la Apoptosis , Síndrome de Beckwith-Wiedemann/patología , Cromosomas Humanos Par 11/genética , Metilación de ADN/genética , Femenino , Impresión Genómica/genética , Mutación de Línea Germinal/genética , Humanos , Recién Nacido , Enfermedades del Recién Nacido/genética , Enfermedades del Recién Nacido/fisiopatología , Herencia Materna , Linaje , Embarazo , Arginina Deiminasa Proteína-Tipo 6 , Síndrome de Silver-Russell/fisiopatología
6.
J Pediatr Gastroenterol Nutr ; 66(2): 306-311, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28806298

RESUMEN

OBJECTIVES: Nutritional management of children with Silver-Russell syndrome (SRS) is crucial, especially before initiating growth hormone therapy. Since cyproheptadine (CYP) has been reported to be orexigenic, we retrospectively investigated the effects of CYP on changes in weight and height in patients with SRS. METHODS: Anthropometric parameters (weight [W], length or height [H], weight on expected weight for height [W/H], and body mass index) were recorded for 34 children with SRS receiving CYP. We specifically analyzed the anthropometric parameters (expressed in median) in a group of 23 patients treated with CYP at baseline (M0-CYP) and every 3 months (M3 to M12-CYP) after the initiation of CYP treatment. RESULTS: The 23 children with SRS treated by CYP only had weight stagnation during the months preceding the start of treatment. Anthropometric parameters, especially the weight, differed significantly between M0-CYP and all other times (M3, M6, M9, M12-CYP). After 1 year of treatment, a gain in overall length/height and weight was observed (W: +1.1 standard deviations from the mean [SDS]; H: +0.5 SDS). At M3, significant improvements in W/H (74.9% vs 79.3% [P = 0.01]) and body mass index (-3.4 vs -2.4 SDS [P = 0.001]) were also observed. Twenty-one patients (91%) improved their weight by at least +0.5 SDS, and 12 (52%) by at least +1 SDS. CONCLUSIONS: Our results show that CYP can be effective in patients with SRS with significant improvements in growth velocity and nutritional status before initiation of growth hormone therapy. Further prospective studies are required to confirm these results.


Asunto(s)
Desarrollo Infantil/efectos de los fármacos , Ciproheptadina/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Síndrome de Silver-Russell/tratamiento farmacológico , Antropometría/métodos , Preescolar , Femenino , Estudios de Seguimiento , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/etiología , Humanos , Lactante , Masculino , Estudios Retrospectivos , Síndrome de Silver-Russell/fisiopatología
7.
J Clin Endocrinol Metab ; 102(11): 4100-4108, 2017 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28945864

RESUMEN

Objectives: Premature adrenarche has been reported to be frequent in Silver-Russell syndrome (SRS), but systematic studies are lacking. Here, we studied the prevalence of early adrenarche in SRS, potential predictors, and consequences based on cases with long-term follow-up. Design and Setting: This retrospective longitudinal single-center study included 62 patients with SRS (34 boys) with documented age at adrenarche and positive Netchine-Harbison clinical score who were seen during the past 20 years with a median follow-up of 12.8 years. Clinical and biochemical characteristics were collected from patient records. Adrenarche was defined by reaching a serum dehydroepiandrosterone concentration >500 ng/mL. Results: Boys reached adrenarche at a median age of 9.2 years (quartiles: 7.6, 10.9 years) and pubarche at a median age of 11.7 years (quartiles: 10.7, 12.8 years). Girls reached adrenarche at a median age of 8.1 years (quartiles: 6.6, 10.1 years) and pubarche at a median age of 9.8 years (quartiles: 8.3, 10.8). Premature adrenarche occurred in 13% of the patients. Multiple linear regression analysis revealed that early adrenarche was associated with early initiation of recombinant human growth hormone (rhGH) treatment (P = 0.0024 in boys; P = 0.0195 in girls), but not with the Netchine-Harbison clinical score (P > 0.25). Response to rhGH treatment (median dose, 50 µg/kg/d) and adult height (n = 43) were not compromised by early adrenarche. Conclusions: Early or premature adrenarche was more frequent in SRS than in the general population and was associated with early age at initiation of rhGH treatment. Response to rhGH treatment and adult height were not compromised by early adrenarche.


Asunto(s)
Adrenarquia/fisiología , Síndrome de Silver-Russell/fisiopatología , Adolescente , Adrenarquia/efectos de los fármacos , Factores de Edad , Niño , Deshidroepiandrosterona/sangre , Femenino , Estudios de Seguimiento , Terapia de Reemplazo de Hormonas , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Estudios Longitudinales , Masculino , Pubertad Precoz/sangre , Pubertad Precoz/tratamiento farmacológico , Pubertad Precoz/fisiopatología , Estudios Retrospectivos , Síndrome de Silver-Russell/tratamiento farmacológico , Factores de Tiempo
8.
Neonatal Netw ; 36(4): 206-212, 2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28764823

RESUMEN

Silver-Russell syndrome (SRS) is a rare congenital imprinting disorder. The genetic findings in SRS patients are heterogeneous and often sporadic. However, chromosomes 7, 11, and 17 are consistently involved in all individuals who meet the strict diagnostic criteria of SRS. There are many clinical features characteristic of SRS; the most common are low birth weight, short stature, triangular face, clinodactyly, relative macrocephaly, ear anomalies, and skeletal asymmetry.


Asunto(s)
Enfermedades del Recién Nacido/fisiopatología , Enfermedades del Recién Nacido/terapia , Síndrome de Silver-Russell/fisiopatología , Síndrome de Silver-Russell/terapia , Educación Continua en Enfermería , Femenino , Humanos , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico , Enfermedades del Recién Nacido/genética , Masculino , Fenotipo , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética
9.
Hum Mol Genet ; 25(24): 5407-5417, 2016 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-27798108

RESUMEN

Silver Russell Syndrome (SRS) syndrome is an imprinting disorder involving low birth weight with complex genetics and diagnostics. Some rare SRS patients carry maternally inherited microduplications spanning the imprinted genes CDKN1C, PHLDA2, SLC22A18 and KCNQ1, suggesting that overexpression of one of more of these genes contributes to the SRS phenotype. While this molecular alteration is very rare, feeding difficulties are a very common feature of this condition. Given that SRS children also have very low body mass index, understanding the underpinning biology of the eating disorder is important, as well as potential co-occurring behavioural alterations. Here, we report that a mouse model of this microduplication exhibits a number of behavioural deficits. The mice had a blunted perception of the palatability of a given foodstuff. This perception may underpin the fussiness with food. We additionally report hypoactivity, unrelated to anxiety or motoric function, and a deficit in the appropriate integration of incoming sensory information. Importantly, using a second genetic model, we were able to attribute all altered behaviours to elevated expression of a single gene, Cdkn1c. This is the first report linking elevated Cdkn1c to altered behaviour in mice. Importantly, the findings from our study may have relevance for SRS and highlight a potentially underreported aspect of this disorder.


Asunto(s)
Conducta Animal/fisiología , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Hipercinesia/genética , Síndrome de Silver-Russell/genética , Animales , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/biosíntesis , Metilación de ADN/genética , Modelos Animales de Enfermedad , Duplicación de Gen , Impresión Genómica , Humanos , Hipercinesia/fisiopatología , Recién Nacido de Bajo Peso , Ratones , Ratones Transgénicos , Síndrome de Silver-Russell/fisiopatología
10.
Curr Opin Pediatr ; 28(4): 529-35, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27386972

RESUMEN

PURPOSE OF REVIEW: The purpose of review is to summarize new outcomes for the clinical characterization, molecular strategies, and therapeutic management of Silver-Russell syndrome (SRS). RECENT FINDINGS: Various teams have described the clinical characteristics of SRS patients by genotype. A clinical score for the definition of SRS and for orienting molecular investigations has emerged. Insulin-like growth factor 2 (a major fetal growth factor) has been implicated in the pathophysiology of SRS, as the principle molecular mechanism underlying the disease is loss of methylation of the 11p15 region, including the imprinted insulin-like growth factor 2 gene. Maternal uniparental disomy of chromosome 7 and recently identified rare molecular defects have also been reported in patients with SRS. However, 40% of patients still have no molecular diagnosis. SUMMARY: The definition of SRS has remained clinical since the first description of this condition, despite the identification of various molecular causes. The clinical issues faced by these patients are similar to those faced by other patients born small for gestational age (SGA), but patients with SRS require specific multidisciplinary management of their nutrition, growth, and metabolism, as they usually present an extreme form of SGA. Molecular analyses can confirm SRS, and are of particular importance for genetic counseling and prenatal testing.


Asunto(s)
Metilación de ADN , Impresión Genómica , Síndrome de Silver-Russell , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Asesoramiento Genético/métodos , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Fenotipo , Guías de Práctica Clínica como Asunto , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/fisiopatología
11.
Artículo en Inglés | MEDLINE | ID: mdl-26615046

RESUMEN

Silver-Russell syndrome (SRS) is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alternations. It is characterized by prenatal and postnatal growth retardation, relative macrocephaly, the triangular face and body asymmetry. About 40-60% of cases are caused by hypomethylation of 11p.15.5 Imprinting Centre Region 1 (ICR1) on the paternal chromosome, and maternal uniparental disomy for chromosome 7 (UPD(7)mat) is found in 5-10% of cases. There are suggested correlations between genotype and the phenotype. Psychomotor development may be delayed, usually mildly, with school difficulties and speech delay more common in patients with UPD(7)mat. Children with 11p15 hypomethylation are shorter and lighter at birth in comparison to children with UPD(7)mat, however further deceleration tends to be more apparent in the latter group. The onset of puberty tends to occur early, with acceleration of bone age, resulting in less apparent growth spurt. Failure to thrive and feeding problems are characteristic for the infant period, and further development of a child may be conditioned by additional congenital defects.


Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 7 , Epigenómica , Predisposición Genética a la Enfermedad , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/fisiopatología , Adolescente , Niño , Preescolar , Femenino , Antecedentes Genéticos , Impresión Genómica , Humanos , Lactante , Masculino
12.
Neuro Endocrinol Lett ; 35(4): 306-13, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25038594

RESUMEN

OBJECTIVE: Silver-Russell syndrome is heterogeneous both clinically and genetically. The best known genetic aberrations existing in this syndrome are an 11p15 epimutation, present in 20-60% patients, and a maternal uniparental chromosome 7 disomy (7-15%) (upd(7)mat). Children with SRS suffer from physical growth impairments - intrauterine and after birth. MATERIAL AND METHODS: The study group consisted of 38 children aged 2 to 17 (x=8.9 ± 4.0 years). These children had undergone a genetic analysis in search for the 11p15 epimutation and the upd(7)mat. Somatic growth was also analysed in terms of birth parameters and postnatal BMI, weight and height. The aforementioned parameters were compared in a subgroup of children with the genetic aberrations and with a control group of children born with IUGR. RESULTS: In the study group a mean weight SD on birth was -3.41 ± 1.22, the birth height was -1.25 ± 2.08 SD and a head circumference of -3.56 ± 1.93 SD. No significant differences were noted between the SRS study group and the control group in reference to weight and head circumference (p>0.05). Such difference was, however, seen in birth height. Children with 11p15 epimutation had significantly lower weight and height at birth, but a significantly larger head circumference than children without this genetic aberration. When analysing further development of children with SRS, a significantly smaller height SD, body mass and BMI was observed, compared with children from the control group. CONCLUSIONS: Children with SRS present impaired somatic development compared to children with IUGR, and these with a genetic aberration develop worse.


Asunto(s)
Desarrollo Infantil/fisiología , Retardo del Crecimiento Fetal/fisiopatología , Síndrome de Silver-Russell/fisiopatología , Adolescente , Peso al Nacer/fisiología , Estatura/fisiología , Índice de Masa Corporal , Niño , Preescolar , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 7/genética , Femenino , Marcadores Genéticos/genética , Humanos , Masculino , Polonia , Distribución Aleatoria , Síndrome de Silver-Russell/genética , Factores de Tiempo
13.
Artículo en Inglés | MEDLINE | ID: mdl-24296634

RESUMEN

BACKGROUND: Hypomethylation of the imprinting control region 1 (ICR 1) at the IGF2/H19 locus on 11p15 is linked to Silver-Russel syndrome (SRS). METHODS AND RESULTS: We tested the hypothesis that the severity of the phenotype in SRS patients is dependent on the clinical severity score (CSS) (1). Three SRS patients were clinically scored and their scores ranged between 12, 13 and 13. Two of the three SRS patients (66%) had hypomethylation of one allele. CONCLUSION: All three patients had high CSS. Nevertheless, only two of them had hypomethylation of one H19 allele. Interestingly, two of them had ventricular septal defects, but only one had H19 hypomethylation. All children had low birth length and weight, a classic facial phenotype, haemihypertrophy (>2.5 cm thinner left arm/leg in comparison to the right one), shorter leg, and striking thinness (BMI of >16.0). One child was operated for cryptorchidismus, and the same child had elbow contracture. Two children had scoliosis. All three children were short (-3 to 5.5 SD), and treatment with GH resulted in growth on the third percentile. Since one child had no hypomethylation and two had a lower degree of hypomethylation, the higher CSS (12, 13 and 13) was not followed by a higher degree of hypomethylation of the IGF2/H19 locus.


Asunto(s)
Metilación de ADN , ARN Largo no Codificante/genética , Síndrome de Silver-Russell/genética , Adolescente , Desarrollo del Adolescente , Factores de Edad , Niño , Desarrollo Infantil , Preescolar , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Fenotipo , Reacción en Cadena de la Polimerasa , Canales de Potasio con Entrada de Voltaje/genética , Pronóstico , Regiones Promotoras Genéticas , Índice de Severidad de la Enfermedad , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/fisiopatología , Síndrome de Silver-Russell/terapia
14.
J Med Genet ; 50(12): 823-30, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24065356

RESUMEN

BACKGROUND: Russell Silver syndrome (RSS) leads to prenatal and postnatal growth retardation. About 55% of RSS patients present a loss-of-methylation of the paternal ICR1 domain on chromosome 11p15. CDKN1C is a cell proliferation inhibitor encoded by an imprinted gene in the 11p15 ICR2 domain. CDKN1C mutations lead to Beckwith Wiedemann syndrome (BWS, overgrowth syndrome) and in IMAGe syndrome which associates growth retardation and adrenal insufficiency. We searched for CDKN1C mutations in a cohort of clinically diagnosed RSS patients with no molecular anomaly. METHOD: The coding sequence and intron-exon boundaries of CDKN1C were analysed in 97 RSS patients. The impact of CDKN1C variants on the cell cycle in vitro were determined by flow cytometry. Stability of CDKN1C was studied by western immunoblotting after inhibition of translation with cycloheximide. RESULTS: We identified the novel c.836G>[G;T] (p.Arg279Leu) mutation in a familial case of intrauterine growth retardation (IUGR) with RSS phenotype and no evidence of IMAGe. All the RSS patients inherited this mutation from their mothers (consistent with monoallelic expression from the maternal allele of the gene). A mutation of this amino acid (p.Arg279Pro) has been reported in cases of IMAGe. Functional analysis showed that Arg279Leu (RSS) did not affect the cell cycle, whereas the Arg279Pro mutation (IMAGe) led to a gain of function. Arg279Leu (RSS) led to an increased stability which could explain an increased activity of CDKN1C. CONCLUSIONS: CDKN1C mutations cause dominant maternally transmitted RSS, completing the molecular mirror with BWS. CDKN1C should be investigated in cases with family history of RSS.


Asunto(s)
Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Mutación/genética , Antígeno Nuclear de Célula en Proliferación/genética , Síndrome de Silver-Russell/genética , Secuencia de Aminoácidos , Análisis de Varianza , Sitios de Unión/genética , Simulación por Computador , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Retardo del Crecimiento Fetal/genética , Células HeLa , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Antígeno Nuclear de Célula en Proliferación/metabolismo , Alineación de Secuencia , Síndrome de Silver-Russell/fisiopatología
15.
Horm Res Paediatr ; 76(6): 369-78, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22156540

RESUMEN

3-M syndrome is an autosomal recessive primordial growth disorder characterised by severe postnatal growth restriction caused by mutations in CUL7, OBSL1 or CCDC8. Clinical characteristics include dysmorphic facial features and fleshy prominent heels with a variable degree of radiological abnormalities. CUL7 is a structural protein central to the formation of an ubiquitin E3 ligase that is known to target insulin receptor substrate 1 for degradation. CUL7 also binds to p53 and may be involved in the control of p53-dependent apoptosis. OBSL1 is a cytoskeletal adaptor protein that was thought to play a central role in myocyte remodelling, and CCDC8 has no defined function as yet. However, the physical interaction of OBSL1 with both CUL7 and CCDC8 and its potential role in the regulation of CUL7 expression suggest all three proteins are members of the same growth-regulatory pathway. Future work should be directed to investigating the function of the 3-M syndrome pathway and in particular the role in the insulin like growth factor I signalling pathway with a view of potentially revealing new therapeutic targets and identifying key regulators of cellular growth.


Asunto(s)
Desarrollo del Adolescente , Proteínas Portadoras/metabolismo , Desarrollo Infantil , Proteínas Cullin/metabolismo , Proteínas del Citoesqueleto/metabolismo , Enanismo/genética , Enanismo/metabolismo , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Hipotonía Muscular/genética , Hipotonía Muscular/metabolismo , Adolescente , Animales , Estatura , Proteínas Portadoras/genética , Niño , Proteínas Cullin/genética , Proteínas del Citoesqueleto/genética , Enanismo/fisiopatología , Humanos , Discapacidad Intelectual/fisiopatología , Hipotonía Muscular/fisiopatología , Proteínas Mutantes/metabolismo , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/metabolismo , Síndrome de Silver-Russell/fisiopatología , Columna Vertebral/anomalías , Columna Vertebral/metabolismo , Columna Vertebral/fisiopatología
16.
Best Pract Res Clin Endocrinol Metab ; 25(1): 77-100, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21396576

RESUMEN

Normally, one inherits one chromosome of each pair from one parent and the second chromosome from the other parent. Uniparental disomy (UPD) describes the inheritance of both homologues of a chromosome pair from the same parent. The biological basis of UPD syndromes is disturbed genomic imprinting. The consequences of UPD depend on the specific chromosome/segment involved and its parental origin. Phenotypes range from unapparent to unmasking of an autosomal-recessive disease to presentation as a syndromic imprinting disorder. Whilst paternal UPD(7) is clinically unapparent, maternal UPD(7) is one of several causes of Silver-Russell syndrome. Presentation of paternal UPD(14) ("Kagami syndrome") is a thoracic dysplasia syndrome with mental retardation and limited survival. Findings in maternal UPD(14) ("Temple") syndrome show an age-dependent overlap with the well-known maternal UPD(15) (Prader-Willi) syndrome and are dominated by initial failure to thrive followed by obesity, learning difficulties and precocious puberty. Diagnostic strategies to tackle the genetic heterogeneity of UPD(7) and UPD(14) syndromes will be explained. Management issues in UPD(7) and UPD(14) patients will be discussed, and finally areas requiring further research will be outlined.


Asunto(s)
Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 7/genética , Síndrome de Prader-Willi/genética , Síndrome de Silver-Russell/genética , Disomía Uniparental/genética , Niño , Preescolar , Epigenómica , Estudios de Asociación Genética , Impresión Genómica , Humanos , Lactante , Madres , Síndrome de Prader-Willi/fisiopatología , Síndrome de Silver-Russell/fisiopatología , Disomía Uniparental/diagnóstico
17.
Br J Ophthalmol ; 95(5): 637-41, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-20805133

RESUMEN

AIM: To evaluate ophthalmological findings in children with Silver-Russell syndrome (SRS). METHODS: An ophthalmological evaluation including visual acuity (VA), refraction, strabismus, near point of convergence (NPC), slit-lamp examination, ophthalmoscopy, axial length measurements and full-field electroretinogram was performed on 18 children with SRS (8 girls, 10 boys; mean age 11.6 years). Fundus photographs were taken for digital image analysis. Data were compared with data on an age- and gender-matched reference group (ref) of school children (n=99). RESULTS: Seventeen out of 18 children with SRS had ophthalmological abnormalities. Best corrected VA of the best eye was <0.1 log of the minimal angle of resolution in 11 children (ref n=98) (p<0.0001), and 11 children had refractive errors (ref n=33) (p=0.05). Anisometropia (≥1 dioptre) was noted in three of the children (ref n=3) (p=0.046). Subnormal stereo acuity and NPC were found in 2/16 (ref=0) (p=0.02). The total axial length in both eyes was shorter compared with that in controls (p<0.006 and p<0.001). Small optic discs were found in 3/16, large cup in 3/16 and increased tortuosity of retinal vessels in 4/13 children with SRS. CONCLUSION: Children with SRS, who are severely intrauterine growth retarded, show significant ophthalmological abnormalities. Based on the present findings, ophthalmological examination is recommended in children with SRS.


Asunto(s)
Síndrome de Silver-Russell/complicaciones , Estrabismo/etiología , Agudeza Visual/fisiología , Adolescente , Niño , Preescolar , Electrorretinografía/métodos , Femenino , Humanos , Masculino , Estudios Prospectivos , Refracción Ocular/fisiología , Síndrome de Silver-Russell/epidemiología , Síndrome de Silver-Russell/fisiopatología , Estrabismo/diagnóstico , Estrabismo/fisiopatología , Suecia/epidemiología
18.
Adv Genet ; 70: 145-75, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20920748

RESUMEN

Genomic imprinting represents a form of epigenetic control of gene expression in which one allele of a gene is preferentially expressed according to the parent-of-origin of the allele. Genomic imprinting plays an important role in normal growth and development. Disruption of imprinting can result in a number of human imprinting syndromes and predispose to cancer. In this chapter, we describe a number of human imprinting syndromes to illustrate the concepts of genomic imprinting and how loss of imprinting of imprinted genes their relationship to human neoplasia.


Asunto(s)
Metilación de ADN , Epigénesis Genética , Regulación de la Expresión Génica , Impresión Genómica , Neoplasias/genética , Animales , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/fisiopatología , Cromatina/genética , Islas de CpG/genética , Variaciones en el Número de Copia de ADN , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatología , Femenino , Humanos , Masculino , Mutación , Técnicas Reproductivas Asistidas/efectos adversos , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/fisiopatología , Síndrome
19.
Orphanet J Rare Dis ; 5: 19, 2010 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-20573229

RESUMEN

Imprinted genes with a parent-of-origin specific expression are involved in various aspects of growth that are rooted in the prenatal period. Therefore it is predictable that many of the so far known congenital imprinting disorders (IDs) are clinically characterised by growth disturbances. A noteable imprinting disorder is Silver-Russell syndrome (SRS), a congenital disease characterised by intrauterine and postnatal growth retardation, relative macrocephaly, a typical triangular face, asymmetry and further less characteristic features. However, the clinical spectrum is broad and the clinical diagnosis often subjective. Genetic and epigenetic disturbances can meanwhile be detected in approximately 50% of patients with typical SRS features. Nearly one tenth of patients carry a maternal uniparental disomy of chromosome 7 (UPD(7)mat), more than 38% show a hypomethylation in the imprinting control region 1 in 11p15. More than 1% of patients show (sub)microscopic chromosomal aberrations. Interestingly, in approximately 7% of 11p15 hypomethylation carriers, demethylation of other imprinted loci can be detected. Clinically, these patients do not differ from those with isolated 11p15 hypomethylation whereas the UPD(7)mat patients generally show a milder phenotype. However, an unambiguous (epi)genotype-phenotype correlation can not be delineated.We therefore suggest a diagnostic algorithm focused on the 11p15 hypomethylation, UPD(7)mat and cryptic chromosomal imbalances for patients with typical SRS phenotype, but also with milder clinical signs only reminiscent for the disease.


Asunto(s)
Impresión Genómica/fisiología , Trastornos del Crecimiento/fisiopatología , Síndrome de Silver-Russell/fisiopatología , Disomía Uniparental/fisiopatología , Algoritmos , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 11/fisiología , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 7/fisiología , Metilación de ADN/genética , Metilación de ADN/fisiología , Impresión Genómica/genética , Trastornos del Crecimiento/genética , Humanos , Síndrome de Silver-Russell/genética , Disomía Uniparental/genética
20.
Horm Res Paediatr ; 74(4): 259-66, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20431273

RESUMEN

BACKGROUND/AIMS: There is limited information about adult height (AH) outcomes and the factors influencing outcomes of growth hormone (GH) therapy in short children born small for gestational age (SGA). METHODS: AH (SDS) and Δheight (SDS) from GH start to AH were analyzed in 161 SGA children who had reached AH (55 with Silver-Russell syndrome, SRS). RESULTS: SGA patients treated to AH were started on GH (median) 0.25 mg/kg/week at an age of 7.8 years with a height of -3.8 SDS. AH after 7.7 years was -2.2 SDS and -1.1 SDS below mid-parental height (MPH). AH (SDS) was explained by: height (SDS) at GH start (+), Δheight (SDS) 1st year on GH (+), years on GH (+), maternal height (SDS) (+), length (SDS) at birth (+), and the diagnosis of SRS (-) (explained variability 70%; error 0.6 SD). Gain in height (SDS) was explained by: Δheight (SDS) 1st year on GH (+), years on GH (+), height - MPH (SDS) at GH start (-) (explained variability 60%; error 0.7 SD). CONCLUSIONS: Algorithms for AH outcomes provides useful information about the potential of long-term growth on GH in short children born SGA.


Asunto(s)
Estatura/efectos de los fármacos , Retardo del Crecimiento Fetal/tratamiento farmacológico , Trastornos del Crecimiento/epidemiología , Hormona de Crecimiento Humana/uso terapéutico , Síndrome de Silver-Russell/tratamiento farmacológico , Niño , Preescolar , Bases de Datos Factuales , Femenino , Retardo del Crecimiento Fetal/etiología , Retardo del Crecimiento Fetal/fisiopatología , Estudios de Seguimiento , Encuestas Epidemiológicas , Humanos , Lactante , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Masculino , Padres , Proteínas Recombinantes/uso terapéutico , Síndrome de Silver-Russell/fisiopatología , Factores de Tiempo , Resultado del Tratamiento
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