RESUMEN

Arthrochalasia Ehlers-Danlos syndrome (aEDS) is a rare autosomal dominant connective tissue disorder that is characterized by congenital bilateral hip dislocations, severe generalized joint hypermobility, recurrent joint (sub)luxations, and skin hyperextensibility. To date, 42 patients with aEDS have been published. We report 12 patients with aEDS from 10 families with 6 unpublished individuals and follow-up data on 6 adult patients. The clinical features are largely comparable with patients reported in the literature. Most (n = 10) patients had variants leading to (partial) loss of exon 6 of the COL1A1 or COL1A2 genes. One patient did not have a previously reported likely pathogenic COL1A1 variant. Data regarding management were retrieved. Hip surgery was performed in 5/12 patients and 3/12 patients underwent spinal surgery. As much as 4/12 patients were wheelchair-bound or unable to walk unaided. Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment. Echocardiograms were performed in 10 patients and 2 individuals showed an abnormality likely unrelated to aEDS. One patient gave birth to two affected children and went through preterm labor requiring medication but had no additional complications. Of the eight adults in our cohort, the majority entered a career. Our data point toward a genotype-phenotype relationship with individuals with aEDS due to pathogenic COL1A1 variants causing complete or partial loss of exon 6 being more severely affected regarding musculoskeletal features. There is a significant lack of knowledge with regard to management of aEDS, particularly in adulthood. As such, systematic follow-up and multidisciplinary treatment is essential.

Asunto(s)

Colágeno Tipo I/genética , Síndrome de Ehlers-Danlos/genética , Luxación Congénita de la Cadera/genética , Adolescente , Adulto , Niño , Preescolar , Cadena alfa 1 del Colágeno Tipo I , Síndrome de Ehlers-Danlos/epidemiología , Síndrome de Ehlers-Danlos/fisiopatología , Exones/genética , Femenino , Predisposición Genética a la Enfermedad , Luxación Congénita de la Cadera/epidemiología , Luxación Congénita de la Cadera/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Linaje , Fenotipo , Anomalías Cutáneas/genética , Anomalías Cutáneas/fisiopatología , Adulto Joven

RESUMEN

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

Asunto(s)

Anomalías Múltiples/genética , Aracnodactilia/genética , Artrogriposis/genética , Blefarofimosis/genética , Fisura del Paladar/genética , Pie Equinovaro/genética , Enfermedades del Tejido Conjuntivo/genética , Contractura/genética , Deformidades Congénitas de la Mano/genética , Canales Iónicos/genética , Oftalmoplejía/genética , Enfermedades de la Retina/genética , Anomalías Múltiples/patología , Aracnodactilia/patología , Artrogriposis/patología , Blefarofimosis/patología , Niño , Preescolar , Fisura del Paladar/patología , Pie Equinovaro/patología , Enfermedades del Tejido Conjuntivo/patología , Contractura/patología , Exoma/genética , Femenino , Deformidades Congénitas de la Mano/patología , Humanos , Masculino , Mutación , Oftalmoplejía/patología , Linaje , Enfermedades de la Retina/patología

RESUMEN

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.

Asunto(s)

Anomalías Múltiples/etiología , Síndrome Branquio Oto Renal/etiología , Displasia Ectodérmica/etiología , Exoma/genética , Hipospadias/etiología , Hipotonía Muscular/etiología , Mutación Missense/genética , Proteínas Represoras/genética , Anomalías Múltiples/patología , Secuencia de Aminoácidos , Síndrome Branquio Oto Renal/patología , Proteínas Co-Represoras , Oído Externo/anomalías , Oído Externo/patología , Displasia Ectodérmica/patología , Femenino , Humanos , Hipospadias/patología , Masculino , Datos de Secuencia Molecular , Hipotonía Muscular/patología , Pezones/anomalías , Pezones/patología , Linaje , Fenotipo , Estructura Terciaria de Proteína , Cuero Cabelludo/anomalías , Cuero Cabelludo/patología , Homología de Secuencia de Aminoácido

RESUMEN

We report here a child with a ring chromosome 5 (r(5)) associated with facial dysmorphology and multiple congenital abnormalities. Fluorescent in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones was performed to determine the breakpoints involved in the r(5). The 5p deletion extended from 5p13.2-3 to 5pter and measured 34.61 Mb (range: 33.7-35.52 Mb) while the 5q deletion extended from 5q35.3 to 5qter and measured 2.44 Mb (range: 2.31-2.57 Mb). The patient presented signs such as microcephaly, hypertelorism, micrognathia and epicanthal folds, partially recalling those of a deletion of the short arm of chromosome 5 and the "cri-du-chat" syndrome. The most striking phenotypic features were the congenital heart abnormalities which have been frequently reported in deletions of the distal part of the long arm of chromosome 5 and in rings leading to a 5q35-5qter deletion. However, the NKX2-5 gene, which has been related to congenital heart defects, was not deleted in our patient, nor presumably to some other patients with 5q35.3-5qter deletion. We propose that VEGFR3, deleted in our patient, could be a candidate gene for the congenital heart abnormalities observed.

Asunto(s)

Anomalías Múltiples/genética , Cromosomas Humanos Par 5/genética , Cromosomas en Anillo , Niño , Análisis Citogenético , Cara/anomalías , Cardiopatías Congénitas/genética , Humanos , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genética

RESUMEN

The 3M syndrome is a rare autosomal recessive disorder recently ascribed to mutations in the CUL7 gene and characterized by severe pre- and postnatal growth retardation. Studying a series of 33 novel cases of 3M syndrome, we have identified deleterious CUL7 mutations in 23/33 patients, including 19 novel mutations and one paternal isodisomy of chromosome 6 encompassing a CUL7 mutation. Lack of mutations in 10/33 cases and exclusion of the CUL7 locus on chromosome 6p21.1 in six consanguineous families strongly support the genetic heterogeneity of the 3M syndrome.

Asunto(s)

Anomalías Múltiples/genética , Proteínas Cullin/genética , Heterogeneidad Genética , Mutación , Niño , Preescolar , Consanguinidad , Familia , Retardo del Crecimiento Fetal/genética , Feto/diagnóstico por imagen , Feto/patología , Genes Recesivos , Humanos , Masculino , Radiografía , Síndrome

RESUMEN

Rubinstein-Taybi syndrome (RSTS) is a rare malformation disorder caused by mutations in the closely related CREBBP and EP300 genes, accounting respectively for up to 60 and 3% of cases. About 10% of CREBBP mutations are whole gene deletions often extending into flanking regions. Using FISH and microsatellite analyses as a first step in the CREBBP mutation screening of 42 Italian RSTS patients, we identified six deletions, three of which were in a mosaic condition that has not been previously reported in RSTS. The use of region-specific BAC clones and small CREBBP probes allowed us to assess the extent of all of the deletions by mapping their endpoints to genomic intervals of 5-10 kb. Four of our five intragenic breakpoints cluster at the 5' end of CREBBP, where there is a peak of breakpoints underlying rearrangements in RSTS patients and tumors. The search for genomic motifs did not reveal any low-copy repeats (LCRs) or any greater density of repetitive sequences. In contrast, the percentage of interspersed repetitive elements (mainly Alu and LINEs in the CREBBP exon 2 region) is significantly higher than that in the entire gene or the average in the genome, thus suggesting that this characteristic may be involved in the region's vulnerability to breaking and nonhomologous pairing. The FISH analysis extended to the EP300 genomic region did not reveal any deletions. The clinical presentation was typical in all cases, but more severe in the three patients carrying constitutional deletions, raising a question about the possible underdiagnosis of a few cases of mild RSTS.

Asunto(s)

Proteína de Unión a CREB/genética , Células Germinativas/fisiología , Síndrome de Rubinstein-Taybi/genética , Eliminación de Secuencia , Adulto , Proteína de Unión a CREB/metabolismo , Mapeo Cromosómico , Femenino , Humanos , Recién Nacido , Síndrome de Rubinstein-Taybi/patología

Asunto(s)

Piebaldismo/genética , Proteínas Proto-Oncogénicas c-kit/genética , Factor de Células Madre/genética , Pruebas Genéticas , Humanos , Factores de Transcripción de la Familia Snail , Factores de Transcripción

RESUMEN

Williams syndrome is a well-recognized disorder, having an incidence of 1 in 20,000 live births. However, thyroid function in these patients is rarely studied. This paper reports thyroid hypoplasia of the left lobe in two girls affected by Williams syndrome, suggesting that it may be a feature of this syndrome.

Asunto(s)

Enfermedades de la Tiroides/patología , Glándula Tiroides/anomalías , Síndrome de Williams/patología , Niño , Preescolar , Femenino , Humanos , Radiografía , Cintigrafía , Enfermedades de la Tiroides/diagnóstico por imagen , Glándula Tiroides/diagnóstico por imagen , Ultrasonografía

RESUMEN

We have recently introduced a new protocol for analyzing all core loci of the Federal Bureau of Investigation's (FBI) Combined DNA Index System (CODIS) with an infrared (IR) automatic DNA sequencer (LI-COR 4200). The amplicons were labeled with forward oligonucleotide primers, covalently linked to a new infrared fluorescent molecule (IRDye 800). The alleles were displayed as familiar autoradiogram-like images with real-time detection. This protocol was employed for paternity testing, population studies, and identification of degraded forensic samples. We extensively analyzed some simulated forensic samples and mixed stains (blood, semen, saliva, bones, and fixed archival embedded tissues), comparing the results with donor samples. Sensitivity studies were also performed for the four multiplex systems. Our results show the efficiency, reliability, and accuracy of the IR system for the analysis of forensic samples. We also compared the efficiency of the multiplex protocol with ultraviolet (UV) technology. Paternity tests, undegraded DNA samples, and real forensic samples were analyzed with this approach based on IR technology and with UV-based automatic sequencers in combination with commercially-available kits. The comparability of the results with the widespread UV methods suggests that it is possible to exchange data between laboratories using the same core group of markers but different primer sets and detection methods.

Asunto(s)

Dermatoglifia del ADN/métodos , Medicina Legal/instrumentación , Análisis de Secuencia de ADN/instrumentación , Fluorescencia , Medicina Legal/métodos , Humanos , Indoles , Rayos Infrarrojos , Reacción en Cadena de la Polimerasa , Sensibilidad y Especificidad , Análisis de Secuencia de ADN/métodos

RESUMEN

Differently from conventional primary neuroectodermal tumors (PNETs), molecular features of undifferentiated lesions have been poorly studied. Medulloblastoma and PNET neoplasms showed a high incidence of loss of heterozygosity (LOH) on chromosome 17p13, in the region of tumor suppressor gene p53. Recent studies have shown a significant correlation between the presence of p53 Arg72Pro polymorphism and several undifferentiated carcinomas. We performed molecular analysis in an anaplastic tumor of posterior fossa in a patient with a constitutional maternal translocation [46,XX,t(5;19)] and a history of headache, nausea and vomiting. We identified the presence of LOH at 17p13 and Pro72Arg polymorphism in tumor DNA. These molecular findings helped us better characterize this undifferentiated tumor and led to a more aggressive therapy.

Asunto(s)

Neoplasias Cerebelosas/genética , Genes p53/genética , Pérdida de Heterocigocidad , Meduloblastoma/genética , Polimorfismo Genético , Neoplasias Cerebelosas/terapia , Niño , Cromosomas Humanos Par 17 , Diagnóstico Diferencial , Femenino , Cefalea/etiología , Humanos , Imagen por Resonancia Magnética , Meduloblastoma/terapia , Náusea/etiología , Vómitos/etiología

RESUMEN

Molecular cytogenetics allows to verify chromosomal homologies previously hypothesised on the base of banding pattern comparison in different species. So far only the chromosome painting technique has been extensively used in studies of chromosomal evolution. This technique allows to detect only interchromosomal rearrangements. Human and Great Apes chromosomes basically differ by intrachromosomal rearrangements, in particular inversions; with chromosome painting it has just been possible to confirm the origin by fusion of human chromosome 2 and a reciprocal translocation in Gorilla, involving the homologous of chromosome 5 and 17. In order to verify intrachromosomal rearrangements in human chromosomal evolution, chromosome mapping of human loci in non-human primates is a useful approach. We mapped Miller-Diecker, Smith-Magenis and RARA loci localised on human chromosome 17, in Gorilla gorilla, Pongo pygmaeus, Macaca fascicularis and Cercopithecus aethiops. On the base of the obtained results it was possible to verify chromosomal rearrangements previously identified by banding, to achieve new informations about the controversial evolution of human chromosome 17, and to detect the occurrence of a paracentric inversion in the homologous in Cercopithecus aethiops.

Asunto(s)

Anomalías Múltiples/genética , Mapeo Cromosómico , Cromosomas Humanos Par 17 , Hominidae/genética , Animales , Evolución Biológica , Chlorocebus aethiops/genética , Humanos , Macaca fascicularis/genética , Sintenía , Translocación Genética

RESUMEN

Previously, we reported results indicating that nebulin was the gene causing the typical form of autosomal recessive nemaline (rod) myopathy. Here we describe the identification of mutations in the nebulin gene in seven offspring of five families affected by the severe congenital form of nemaline myopathy. One pregnancy was terminated on the grounds of foetal abnormality, while six affected infants died at ages ranging from the first day of life to 19 months. Only three of the six neonates were able to establish spontaneous respiration. Three had arthrogryposis. In three of the five families, the mutations were located in exon 184. These mutations are predicted to cause absence of the C-terminal part of nebulin.

Asunto(s)

Proteínas Musculares/genética , Mutación , Miopatías Nemalínicas/genética , Biopsia , Femenino , Humanos , Inmunohistoquímica , Lactante , Recién Nacido , Masculino , Proteínas Musculares/inmunología , Músculo Esquelético/patología , Linaje

RESUMEN

Allele frequencies for the 13 STRs of the Combined DNA Index System (CODIS) core were obtained from a sample of 188 unrelated individuals living in the area of Florence, Prato and Pistoia (Tuscany, Central Italy).

Asunto(s)

Análisis de Secuencia de ADN/métodos , Secuencias Repetidas en Tándem/genética , Población Blanca/genética , Frecuencia de los Genes , Genética de Población , Humanos , Italia , Espectrofotometría Infrarroja/métodos