[No abstract available

LEOPARD syndrome (LS) is an autosomal dominant syndrome characterized by multiple lentigines and café-au-lait spots, electrocardiographic-conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormalities of the genitalia in males, retardation of growth, and deafness. LS shares many features with Noonan syndrome (NS), in which lentigines and deafness are usually not present. Molecular studies have shown that LS and NS are allelic disorders, caused by different missense mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q22-qter. The clinical diagnosis of LS is generally difficult in the first months of life because the distinctive lentigines are generally not present at birth and develop during childhood. From January 2002 to December 2004, we suspected LS clinically in 10 patients admitted to our genetic counseling services in the first 12 months of life. A PTPN11 gene mutation was detected in 8/10 (80%) patients. In one patient without a PTPN11 mutation a subsequent clinical diagnosis of neurofibromatosis type 1 (NF1) was made, following the evaluation of the mother, who had previously undiagnosed classic NF1. The age of LS patients with PTPN11 mutation ranged between 1 and 11 months (mean age +/- SD 7.5 +/- 3.96 months). Review of the clinical characteristics of patients with LS confirmed by molecular study during the first year of life demonstrates that the diagnosis of LS in the first months of age can be clinically suspected in patients presenting with three main features, that is, characteristic facial features (100%), hypertrophic cardiomyopathy (HCM) (87%), and cafe-au-lait spots (75%). Characteristic facial features can be mild or severe, and consist of hypertelorism, downslanting palpebral fissures, ptosis, and dysmorphic ears. The clinical suspicion of LS may be confirmed by molecular screening for PTPN11 mutations. An early diagnosis of the disease is useful for the prospective care of associated medical problems and for precise genetic counseling.

The 22q11.2 deletion (del22q11.2) syndrome is a genetic condition with wide interfamilial and intrafamilial variability in clinical expression. The aim of the present study was to review the prevalence of parental transmission in our series of patients with del22q11.2, and to analyse clinical findings of the affected parents. Parental transmission of del22q11.2 in our series was 17.2% (15/87), with a preferential maternal transmission (10/15). One or more major features of del22q11.2 were found in all deleted parents, but one of the mothers showed extremely mild clinical anomalies. The present data demonstrate that it should be current policy to test both parents of patients with del22q11.2, irrespective of the parental phenotype, in view of the fact that extremely mild clinical features can be detected in parents of deleted patients. This would provide accurate genetic counselling to del22q11.2 families, as relatively asymptomatic parents must be advised of the 50% risk of transmitting the deletion in a subsequent pregnancy. Various genetic and non-genetic factors, including modifier genes at separate loci, mosaicism, unstable mutations, allelic variations at the haploid locus, chance and environmental interaction, can be hypothesized to be involved in variable clinical expression, even in the same family.

BackgroundPopulation-based surveys on the quality of life of people with Down syndrome (DS) are difficult to perform because of ethical and legal policies regarding privacy and confidential information, but they are essential for service planning. Little is known about the sample size and variability of quality of life of people with DS living in the city of Rome, which has a population of 2.7 million inhabitants. The aim of the present study is to explore the needs and challenges in health, social integration and daily life, of people with DS living in Rome.MethodologyA cross-sectional, census-based survey was conducted in 2006. All family doctors (3016 in total) of the National Health Service were involved by the Statistical Bureau of the Municipality of Rome. As per the census, every resident citizen is registered with a family doctor and every person with disabilities is coded. Associations for Down Syndrome encouraged their members to participate in the research. Questionnaires were completed by families of people with DS, in accordance with privacy laws.FindingsAn initial survey, conducted via a letter and a telephone contact with family doctors, identified 884 people with DS residing in the city of Rome. Data on the medical and social conditions of 518 people with DS, ranging in age from 0 to 64 years, were collected. Some 88% of these were living with their original family; 82.1% had one or more siblings, and 19.5% had lost one or both parents. A full 100% of children with DS were enrolled in the public school system. This ensures that they are fully occupied and entirely integrated in society. After secondary school there is a lack of opportunities. Thus, only 10% of adults were working with a regular contract. A mere 42.2% of people with DS aged 25–30 were involved in some form of regular activity (although not always on a daily basis). After the age of 30, the percentage of people demonstrating decline in function increased sharply, while disability-related support decreased. In other words, as people with DS age, daily life evolves increasingly around the home, with only occasional outdoor activities.ConclusionThe health, employment and social needs of the majority of people with DS in the city of Rome are not being met. The findings of this study underscore the urgent need for more comprehensive inclusion in society of adults with DS and for the provision of support services to create an enabling environment for inclusion. Because of the variability of performance among individuals with DS, there is a need to create more case-specific options in terms of work, living arrangements, social networking and medical services. Schooling and social inclusion in childhood alone do not guarantee a satisfactory quality of life in adulthood. It is argued herewith that policy of inclusion and support should extend over the entire lifetime of people with DS.

The oculo-auriculo-vertebral spectrum (OAVS) is a non-random association of microtia, hemifacial microsomia with mandibular hypoplasia, ocular epibulbar dermoid, and cervical vertebral malformations. Congenital heart defects (CHDs) have been reported in 5-58% of the patients. We analyze the frequency and anatomic features of CHD in a series of 87 patients with OAVS examined between January 1990 and February 2007 with normal chromosomes, ranging in age between 0.1 and 16.8 years. A twin pregnancy occurred in eight cases (dizygotic in six cases and monozygotic in two). CHDs were diagnosed in 28/87 (32%) patients, and classified into categories of postulated developmental mechanisms including 9 (32%) atrial and ventricular septal defects, 11 (39%) conotruncal defects, 4 (14%) targeted growth defects, two (7%) with situs and looping defects, one (4%) with a left-sided obstructive lesion and one (4%) with patent ductus arteriosus. As noted in other series, the most common individual CHDs were ventricular septal defect (six patients) and tetralogy of Fallot (TOF) (classic or with pulmonary atresia) (six patients). Comparing the frequencies of CHDs groups observed in the OAVS patients with the findings of the Emilia-Romagna Registry which ascertained CHDs prevalence in the general population, conotruncal defects, targeted growth defects, and heterotaxia were significantly associated with OAVS.

Conotruncal defects (CTDs) represent 15-20% of all congenital heart defects. Mutations in a number of genes have been associated with CTD in humans and animal models. We investigated the occurrence and the prevalence of GATA4, NKX2.5, ZFPM2/FOG2, GDF1, and ISLET1 gene mutations in a large cohort of individuals with CTD, including tetralogy of Fallot with or without pulmonary atresia (TOF, 178 patients), double outlet right ventricle (DORV, 13 patients), and truncus arteriosus (11 patients). Denaturing high-performance liquid chromatography (DHPLC) analysis followed by bidirectional sequencing disclosed no putative pathogenic mutation in GATA4, ISLET1, and GDF1 genes. Two novel (Ile227Val, Met544Ile) and one previously reported (Glu30Gly) possibly pathogenic missense variants were identified in the ZFPM2/FOG2 gene in 3 sporadic patients of 202 (1.5%) with CTD, including 1 of 178 (0.6%) with TOF and 2 of 13 (15.4%) with DORV. Mutation analysis also detected one known missense change (Arg25Cys) in NKX2.5 gene in two (1.1%) sporadic patients with TOF. These sequence alterations were found to be absent in 500 population-matched controls. In conclusion, the present results (i) indicate and confirm that mutations in the GATA4, GDF1, and ISLET1 genes are not major determinants in the pathogenesis of TOF, (ii) provide supportive evidence of an association between ZFPM2/FOG2 gene and TOF/DORV, and (iii) provide additional examples of the possible contribution of the Arg25Cys change in the NKX2.5 to a small number of TOF cases.

In children with Noonan syndrome and left ventricular hypertrophy a careful echocardiographic assessment of the mitral valve should reveal those in whom the left ventricular outflow tract obstruction is anatomical in nature.

SUMMARYChromosome 22q11.2 deletion ( del22q11.2 ) syndrome (DiGeorge syndrome/velocardiofacial syndrome) is a common syndrome typically consisting of congenital heart disease, hypoparathyroidism, developmental delay and immunodeficiency. Although a broad range of immunologic defects have been described in these patients, limited information is currently available on the diversity of the T-cell receptor (TCR) variable b (BV) chain repertoire. The TCRBV repertoires of nine patients with del22q11.2 syndrome were determined by flow cytometry, fragment size analysis of the third complementarity determining region (CDR3 spectratyping) and sequencing of V(D)J regions. The rate of thymic output and the phenotype and function of peripheral T cells were also studied. Expanded TCRBV families were detected by flow cytometry in both CD4 + and CD8 + T cells. A decreased diversity of TCR repertoires was also demonstrated by CDR3 spectratyping, showing altered CDR3 profiles in the majority of TCRBV families investigated. The oligoclonal nature of abnormal peaks detected by CDR3 spectratyping was confirmed by the sequence analysis of the V(D)J regions. Thymic output, evaluated by measuring TCR rearrangement excision circles (TRECs), was significantly decreased in comparison with age-matched controls. Finally, a significant up-regulation in the percentage, but not in the absolute count, of activated CD4 + T cells (CD95 + , CCR5 + , HLA-DR + ), IFN-g -and IL-2-expressing T cells was detected. These findings suggest that the diversity of CD4 and CD8 TCRBV repertoires is decreased in patients with del22q11.2 syndrome, possibly as a result of either impaired thymic function and/or increased T-cell activation.