RESUMEN
The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.
Asunto(s)
Pruebas Genéticas/métodos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Adolescente , Adulto , Niño , Preescolar , Hibridación Genómica Comparativa , Análisis Citogenético , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Análisis de Secuencia de ADN , Inactivación del Cromosoma X , Adulto JovenRESUMEN
BACKGROUND: Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. METHOD: Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. RESULTS: 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. CONCLUSION: Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.
Asunto(s)
Cerebro/anomalías , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Proteínas de Dominio MADS/genética , Factores Reguladores Miogénicos/genética , Trastorno de Movimiento Estereotipado/genética , Cerebro/metabolismo , Niño , Preescolar , Haploidia , Humanos , Lactante , Factores de Transcripción MEF2RESUMEN
Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).
Asunto(s)
Síndrome de Cockayne/genética , ADN Helicasas/genética , Enzimas Reparadoras del ADN/genética , Mutación/genética , Factores de Transcripción/genética , Secuencia de Aminoácidos , Síndrome de Cockayne/diagnóstico , ADN Helicasas/química , Enzimas Reparadoras del ADN/química , Bases de Datos Genéticas , Estudios de Asociación Genética , Humanos , Datos de Secuencia Molecular , Proteínas de Unión a Poli-ADP-Ribosa , Polimorfismo Genético , Alineación de Secuencia , Relación Estructura-Actividad , Factores de Transcripción/químicaRESUMEN
The autosomal recessive demyelinating form of Charcot-Marie-Tooth can be due to SH3TC2 gene pathogenic variants (CMT4C, AR-CMTde-SH3TC2). We report on a series of 13 patients with AR-CMTde-SH3TC2 among a French cohort of 350 patients suffering from all type of inheritance peripheral neuropathy. The SH3TC2 gene appeared to be the most frequently mutated gene for demyelinating neuropathy in this series by NGS. Four new pathogenic variants have been identified: two nonsense variants (p.(Tyr970*), p.(Trp1199*)) and two missense variants (p.(Leu1126Pro), p.(Ala1206Asp)). The recurrent variant p.Arg954* was present in 62%, and seems to be a founder mutation. The phenotype is fairly homogeneous, as all these patients, except the youngest ones, presented scoliosis and/or hearing loss.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Sordera/genética , Variación Genética/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Escoliosis/genética , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/epidemiología , Niño , Estudios de Cohortes , Sordera/epidemiología , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Escoliosis/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: Congenital disorders of glycosylation (CDG), or carbohydrate deficient glycoprotein syndromes, form a new group of multisystem disorders characterised by defective glycoprotein biosynthesis, ascribed to various biochemical mechanisms. METHODS: We report the clinical, biological, and molecular analysis of 26 CDG I patients, including 20 CDG Ia, two CDG Ib, one CDG Ic, and three CDG Ix, detected by western blotting and isoelectric focusing of serum transferrin. RESULTS: Based on the clinical features, CDG Ia could be split into two subtypes: a neurological form with psychomotor retardation, strabismus, cerebellar hypoplasia, and retinitis pigmentosa (n=11), and a multivisceral form with neurological and extraneurological manifestations including liver, cardiac, renal, or gastrointestinal involvement (n=9). Interestingly, dysmorphic features, inverted nipples, cerebellar hypoplasia, and abnormal subcutaneous fat distribution were not consistently observed in CDG Ia. By contrast, the two CDG Ib patients had severe liver disease, enteropathy, and hyperinsulinaemic hypoglycaemia but no neurological involvement. Finally, the CDG Ic patient and one of the CDG Ix patients had psychomotor retardation and seizures. The other CDG Ix patients had severe proximal tubulopathy, bilateral cataract, and white matter abnormalities (one patient), or multiorgan failure and multiple birth defects (one patient). CONCLUSIONS: Owing to the remarkable clinical variability of CDG, this novel disease probably remains largely underdiagnosed. The successful treatment of CDG Ib patients with oral mannose emphasises the paramount importance of early diagnosis of PMI deficiency.
Asunto(s)
Trastornos Congénitos de Glicosilación/patología , Tejido Adiposo/anomalías , Adolescente , Adulto , Niño , Preescolar , Trastornos Congénitos de Glicosilación/clasificación , Trastornos Congénitos de Glicosilación/genética , Cara/anomalías , Femenino , Glicoproteínas/sangre , Humanos , Lactante , Masculino , Mutación , Pezones/anomalías , Fosfotransferasas (Fosfomutasas)/genética , Trastornos Psicomotores , Transferrina/metabolismoRESUMEN
We report on two sibs with a multiple congenital anomalies/mental retardation (MCA/MR) syndrome who have a first cousin with Möbius anomaly. This may represent a new MCA/MR syndrome.
Asunto(s)
Anomalías Múltiples/genética , Enfermedades de los Nervios Craneales/genética , Discapacidad Intelectual/genética , Femenino , Humanos , Masculino , Linaje , Fenotipo , Síndrome , Pulgar/anomalías , Dedos del Pie/anomalíasRESUMEN
Rett syndrome (RS) was diagnosed in a girl with a t(X;22) (p11.22;p11). This translocation was also present in her unaffected mother and her sister affected by a neurological disorder compatible with a "forme fruste" of RS. Different etiological mechanisms are considered: gene disruption, X inactivation disturbance, metabolic interference. Whatever this may be, the localization of a RS related gene to the short arm of chromosome X is likely.
Asunto(s)
Cromosomas Humanos Par 22 , Síndrome de Rett/genética , Translocación Genética , Cromosoma X , Niño , Preescolar , Mapeo Cromosómico , Femenino , Humanos , Cariotipificación , Fenotipo , Síndrome de Rett/diagnósticoRESUMEN
Otopalatodigital syndrome type 2 is an X-linked disorder with minimal expression in carrier females and comprises typical facial anomalies and a generalized bone dysplasia with osteodysplastic changes, brachydactyly, and impaired survival. Recently several other severe malformations were reported in the condition. Melnick-Needles syndrome is an X-linked dominant disorder. Affected males are usually sporadic cases. The exceptional males born to symptomatic women present with a lethal disorder comprising generalized osteodysplasia, deficiency of the first ray, and facial anomalies strikingly similar to those of otopalatodigital syndrome type 2. We report here on three boys with classical, severe, and lethal otopalatodigital type 2 syndrome, and three boys with severe (lethal) Melnick-Needles syndrome, born to affected mothers. We suggest that otopalatodigital type 1 and 2, Melnick-Needles syndrome and frontometaphyseal dysplasia, sharing many clinical manifestations and a similar mode of inheritance, are variants of the same condition: fronto-otopalatodigital osteodysplasia. The relationships to similar syndromes (i.e., Saint-Martin-Gardner-Morrisson syndrome, serpentine fibula syndrome, atelosteogenesis type 3, boomerang dysplasia, and Yunis-Varon syndrome) are discussed.
Asunto(s)
Anomalías Múltiples , Huesos/anomalías , Anomalías Craneofaciales , Osteocondrodisplasias , Anomalías Múltiples/diagnóstico por imagen , Adulto , Huesos/diagnóstico por imagen , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Osteocondrodisplasias/diagnóstico por imagen , RadiografíaRESUMEN
Megalocornea (corneal diameter > or = 13 mm) is associated with mental and neurological impairment, and minor anomalies in Neuhäuser syndrome (megalocornea-mental retardation syndrome). Here we report 4 new cases of megalocornea and mental retardation. Those unrelated patients have a consistent pattern of anomalies with possible recessive inheritance which clearly differs from that of the original patients of Neuhäuser et al. [1975]. We discuss the heterogeneity of the syndromes with megalocornea and mental retardation. Based on these cases and on a review of the literature, we suggest a provisional clinically oriented classification in 5 subtypes: (1) a recessive form type Neuhäuser (with iris hypoplasia and minor anomalies), (2) a recessive form type Frank-Temtamy (with camptodactyly, scoliosis and growth retardation), (3) a recessive type 3, including our 4 personal cases (with normal irides, severe hypotonia, relative or absolute macrocephaly and minor anomalies), (4) a possible Frydman type (with normal irides, megalencephaly and obesity), and (5) provisionally unclassifiable cases.
Asunto(s)
Córnea/anomalías , Discapacidad Intelectual/genética , Anomalías Múltiples/clasificación , Anomalías Múltiples/genética , Niño , Preescolar , Humanos , Lactante , Masculino , Fenotipo , SíndromeRESUMEN
Brittany is celtic, like Ireland and Wales where the incidence of neural tube defects is raised. We searched the hospital files in Brittany for all live and still births, and terminations of pregnancy after prenatal diagnosis for the years 1975-1984. 225 cases of spina bifida and 210 cases of anencephaly were identified; giving an incidence of 0.60 per 1000 births for spina bifida and 0.56 per 1000 births for anencephaly. No seasonality was found for both malformations. Analysis of the sex ratio for anencephaly indicated significantly higher proportion of females to males. Maternal age in the affected group was similar to the normal population. Casual heterogeneity among neural tube defects patients was presumed because 14% of our cases had other congenital anomalies.
Asunto(s)
Anencefalia/epidemiología , Espina Bífida Oculta/epidemiología , Anomalías Múltiples/epidemiología , Anencefalia/mortalidad , Femenino , Francia , Humanos , Recién Nacido , Masculino , Edad Materna , Estudios Retrospectivos , Estaciones del Año , Factores Sexuales , Espina Bífida Oculta/mortalidadRESUMEN
Among clinical manifestations of the battered child syndrome, ophthalmic manifestations play a prominent role in the recognition of this syndrome. From personal cases, the authors describe different ocular findings, specially intraocular hemorrhages with the important risk of sequelae. They show the role of the ophthalmologist among several situations. As the ophthalmologist may be the first to examine these traumatized infants his prompt recognition is important to take all necessary steps.
Asunto(s)
Síndrome del Niño Maltratado , Maltrato a los Niños , Lesiones Oculares/etiología , Maltrato a los Niños/psicología , Preescolar , Coriorretinitis/etiología , Femenino , Francia , Humanos , Lactante , Masculino , Padres/psicología , Rol del Médico , Hemorragia Retiniana/etiología , Factores SocioeconómicosRESUMEN
We have studied neural tube malformations in twins in order to research into the role of genetic and environmental factors. 12 pairs of twins in which one child had a neural tube defect were studied in Brittany, which is a Celtic country. We found no evidential agreement about the role each factor played. On the other hand there was an excess of twins in the siblings of those with neural tube defects, especially in the siblings of the mothers. There were more dizygotic twin mothers. Analysing the literature has made it possible for us to find a level of agreement of 7.5% for monozygotic twins and 4.6% for dizygotic twins. This last figure corresponds to the recurrence rate found after one case. The aetiological theories are reviewed. Among factors bringing about neural tube defects would seem to be the microenvironment of the uterus and the delay between ovulation and fertilization and implantation of the fertilized egg. Nutrition of the embryo and possible vitamin deficiencies could explain this inter-action between the mother and the fetus. If there is a genetic factor, it is more likely to be maternal than fetal.
Asunto(s)
Enfermedades en Gemelos , Defectos del Tubo Neural/genética , Anencefalia/genética , Etnicidad , Femenino , Francia , Humanos , Masculino , Defectos del Tubo Neural/etiología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Espina Bífida Oculta/genética , Gemelos Dicigóticos , Gemelos MonocigóticosRESUMEN
We have seen two cases of diprosopy associated with anencephaly in Brittany between 1975 and 1984. Diprosopy is a partial or total duplication of the face. It consists of the phenomenon of late division in the embryo of the cephalic portion of the neural plate between the 16th and the 18th days. This gives rise to an incomplete type of monozygotic twinning or a conjoint twin. There are several different forms of the organs that are duplicated. We have seen a case of diprosopos distomos dirhinos diophthalmos and a case of disprosopos distomos dirhinos triophthalmos. These two cases were associated with anencephaly, the second also having a spina bifida and a diaphragmatic hernia. One can explain the incidence of anencephalies in cases of diprosopies by the desturbance created by the latter on the embryological events that succeed it. The delay in nerve formation makes it impossible for the neural tube to close completely, and this is why sometimes the anencephaly is associated with spina bifida. In more general terms one can postulate that all conjoint twins that are, of course, monozygotic and monochorial can interfere with early enbryological development and increase the risks of failure of the neural tube to close.
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Anomalías Teratoides Graves , Anencefalia/complicaciones , Anomalías Teratoides Graves/patología , Adulto , Anencefalia/patología , Femenino , Humanos , Recién Nacido , EmbarazoRESUMEN
The medical files of 532 patients who underwent medically induced abortion over a 10-year period (1982-1991) in the French department of Ille-et-Vilaine were studied in order to evaluate the indications and outcomes. Among the patients, 358 resided in the department (67%). Comparatively with the number of births during the 10-year period, there was a relative increase in the number of medically induced abortions from 3.5/1000 to 5.5/1000. This parameter was taken into consideration for the interpretation of a parallel decrease in the perinatal mortality during the same period, from 5.9/1000 to 5.1/1000. There was a maternal indication in 91 cases which correspond to the former category of therapeutic induced abortions. There was a clear increase in 1991 corresponding to abortions induced because of extremely premature rupture of the membranes which were formerly allowed to continue to dead births. Foetal indications were frequent: 441 cases (83%). Exogenous causes were lower (15.6%), particularly due to the disappearance of indications resulting from maternal irradiation. For indications related to infection, the vaccination against rubella and improved prenatal diagnosis resulted in the disappearance of rubella as an indication during the last three years of the study and a clear decrease in the number of toxoplasmosis indications. There were few indications due to maternal infection by human immunodeficiency virus (4 cases). Chromosomal abnormalities were the main cause of medically induced abortion among the foetal indications (27.7%).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Aborto Inducido , Aborto Inducido/métodos , Aborto Inducido/estadística & datos numéricos , Aborto Inducido/tendencias , Adolescente , Adulto , Tasa de Natalidad , Aberraciones Cromosómicas/diagnóstico , Aberraciones Cromosómicas/epidemiología , Aberraciones Cromosómicas/prevención & control , Trastornos de los Cromosomas , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/epidemiología , Anomalías Congénitas/prevención & control , Femenino , Rotura Prematura de Membranas Fetales/epidemiología , Francia/epidemiología , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/epidemiología , Enfermedades Genéticas Congénitas/prevención & control , Humanos , Tamizaje Masivo , Edad Materna , Persona de Mediana Edad , Embarazo , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/epidemiología , Embarazo de Alto Riesgo , Características de la Residencia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The authors have studied the different situations that prompt a request for genetic counseling if different members of the same family suffer from cancer. Six possibilities are considered: the cancer concerned is a genetic disease per se (e.g. retinoblastoma, thyroid cancer with amyloid stroma); the genetic disease is often complicated with cancer (e.g. intestinal polyposis); the genetic disease is occasionally complicated with cancer (e.g. neurofibromatosis); cancer is part and parcel of the genetic disease (e.g. chromosomal abnormalities); in addition, there are two special situations: "cancer-prone families" and families who request genetic counseling after one single case (e.g. cancer of leukaemia in a child).
Asunto(s)
Asesoramiento Genético , Enfermedades Genéticas Congénitas/complicaciones , Neoplasias/genética , HumanosRESUMEN
CONTEXT: Heterozygous GNAS inactivating mutations are known to induce pseudohypoparathyroidism type 1a when maternally inherited and pseudopseudohypoparathyroidism when paternally inherited. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, and studies in different families have shown that POH is also caused by paternally inherited GNAS mutations. OBJECTIVE: Our purpose was to characterize parental origin of the mutated allele in de novo cases of POH and to draw phenotype/genotype correlations according to maternal or paternal transmission of a same GNAS mutation. DESIGN AND SETTING: We conducted a retrospective study on patients addressed to our referral center for the rare diseases of calcium and phosphorus metabolism. PATIENTS AND METHODS: We matched 10 cases of POH with cases of pseudohypoparathyroidism type 1a carrying the same GNAS mutations. MAIN OUTCOME MEASURES: The parental origin of the mutated allele was studied using informative intragenic polymorphisms and subcloning of PCR products. RESULTS: Paternal origin of GNAS mutations was clearly demonstrated in eight POH cases including one patient with mutation in exon 1. Genotype/phenotype analyses suggest that there is no direct correlation between the ossifying process and the position of the inactivating GNAS mutation. It is, however, more severe in patients in whom origin of the mutation is paternal. Severe intrauterine growth retardation was clearly evidenced in paternally inherited mutations. CONCLUSIONS: Clinical heterogeneity makes genetic counseling a delicate matter, especially in which paternal inheritance is concerned because it can lead to either a mild expression of pseudopseudohypoparathyroidism or a severe expression of POH.