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[Williams syndrome: memory, visuospatial and visuoconstructive functions].

INTRODUCTION: Williams syndrome (WS) is a dominant autosomal genetic syndrome resulting from a microdeletion on chromosome 7. This deletion gives rise to certain characteristic physical traits, systemic pathologies and a cognitive behavioural pattern that is characterised by the relative preservation of linguistic abilities with very striking visuospatial deficits. CASE REPORTS: We describe the neuropsychological features of three patients with WS, diagnosed by means of a cytogenetic study, and their mnemonic functions and visuospatial skills are explored. CONCLUSIONS: The results obtained in the study of these three patients reinforce the idea, already acknowledged in the literature, of the marked visuospatial difficulties. They also account for the need for an early diagnosis and an extensive knowledge of the cognitive profile of these patients so as to allow the planning of a stimulation that strengthens the cognitive possibilities of children suffering from this syndrome as much as possible.

Adolescent↗
PubMed2003

Genetic counseling.

Medical professionals and the public are rapidly becoming aware of the overwhelming influence that an individual's genetic constitution has on fetal health and mortality, congenital malformations, cancer and other chronic diseases. Great strides have been made in recognizing and understanding modes of inheritance that had not previously been well described. Besides single-gene disorders, genetic conditions are known to be caused by a variety of different mechanisms: chromosome microdeletions and fragility, multifactorial inheritance, mitochondrial genes, triplet repeat expansions, imprinting, and uniparental disomy. Because of the complexity of genetic information, an extensive discussion is often necessary to sort out advertising, news information, and personal health concerns to enable individuals to make decisions for themselves about the various options available for testing and treatment. Genetic counseling has developed as a discipline in response to the need to educate patients, families and professionals about genetic mechanisms and their application in health care. In the future, we anticipate that the emphasis will be on primary care physicians as health-care managers, and genetic counselors will be required to educate individuals about their personal risks of inherited disorders and the implications for future generations. Genetic counseling is a process of medical education based upon empathy, patient autonomy and confidentiality in an atmosphere of empathy, support and understanding. This profession combines the knowledge of complex medical and genetic theory with the skills of a concerned, supportive counselor.

Genetic Counseling↗
PubMed2003

[Genetic cause of male infertility and molecular biology].

At the present time, 15% of couples experience reproduction difficulties. Surgical collection of spermatozoa associated with the intracytoplasmic sperm injection technique (ICSI) resolves the problems of male infertility formerly considered to be irreversible, regardless of its aetiology. Molecular biology now allows evaluation of the genetic dimension of male infertility. Although it demonstrates the multiple aetiologies of male infertility, it also reveals the gaps in our knowledge and the extent of the task that has yet to be accomplished. Microdeletion of the Y chromosome, detected in 2% to 20% of infertile patients with a disorder of spermatogenesis, has already been well documented. All of the genes involved on the Y chromosome (DAZ, RBMY, etc.) in infertile patients have been shown to be involved in spermatogenesis. Testing for other genes of the genome would also be useful. However, the unknown outcome of these abnormalities with successive generations raises a number of questions. In this article, the authors describe the main genes involved in spermatogenesis as demonstrated by molecular biology.

Chromosome Deletion↗
PubMed2004

DNA copy-number analysis of the 22q11 deletion-syndrome region using array-CGH with genomic and PCR-based targets.

Deletions and duplications of genomic segments commonly cause developmental disorders. The resolution and efficiency in diagnosing such gene-dosage alterations can be drastically increased using microarray-based comparative genomic hybridization (array-CGH). However, array-CGH currently relies on spotting genomic clones as targets, which confers severe limitations to the approach including resolution of analysis and reliable gene-dosage assessment of regions with high content of redundant sequences. To improve the methodology for analysis, we compared the use of genomic clones, repeat-free pools of amplified genomic DNA and cDNAs (single and pooled) as targets on the array. For this purpose, we chose q11.2 locus on chromosome 22 as a testing ground. Microdeletions at 22q11 cause birth defects collectively described as the DiGeorge/velocardiofacial syndrome. The majority of patients present 3 Mb typical deletions. Here, we report the construction of a gene-dosage array, covering 6 Mb of 22q11 and including the typically deleted region. We hybridized DNA from six DiGeorge syndrome patients to the array, and show that as little as 11.5 kb non-redundant, repeat-free PCR-generated sequence can be used for reliable detection of hemizygous deletions. By extrapolation, this would allow analysis of the genome with an average resolution of 25 kb. In the case of cDNAs our results indicate that 3.5 kb sequence is necessary for accurate identification of haploid/diploid dosage alterations. Thus, for regions rich in redundant sequences and repeats, such as 22q11, a specifically tailored array-CGH approach is good for gene copy number profiling.

Chromosomes, Human, Pair 22↗
PubMed1992

Opitz-C syndrome: on the nosology of mental retardation and trigonocephaly.

We report on two patients with a complicated form of trigonocephaly. The first patient has the Opitz-"C"-trigonocephaly syndrome. The second patient had initially a delayed motor development, but finally attained normal intelligence. A review of 22 patients with Opitz-C syndrome from the literature is presented. Most of the typical facial dysmorphism can be regarded as part of a trigonocephaly "sequence" rather than presenting characteristic features of a syndrome. More specific are the intra-oral anomalies, abnormally modelled ears, cardiac anomalies and neonatal hypotonia. All surviving patients are severely retarded. Since almost all patients are sporadic cases we suggest that the "C"-syndrome is a cytogenetically yet undetectable microdeletion syndrome.

Abnormalities, Multiple↗
PubMed2003

[Prader-Willi syndrome and genomic imprinting].

OBJECTIVE: Prader-Willi syndrome (PWS) is an example of a human genetic disorder that involves imprinting genes on the proximal long arm of chromosome 15 and SNRPN gene as a candidate gene for this syndrome. The purpose of this study was to show the molecular genetic defects and genomic imprinting basis in Chinese PWS patients and to evaluate the clinical applications of a differential diagnostic test for PWS. METHODS: Fluorescence in situ hybridization (FISH) and methylation-specific PCR (MSPCR) techniques were applied for 4 clinically suspected PWS patients. Using three probes, including SNRPN probe for identification of the critical locus in PWS region, D15Z1 and PML control probes for identification of the 15p arm and 15q arm, the authors detected the deletions 15q in PWS. MSPCR was based on sodium bisulfite treatment of DNA and PCR primers specific for the maternal and paternal allele. RESULTS: When hybridized with mixed probes, it was found in 2 patients that the central specific signal was absent, but both the flanking control signals were retained, indicating SNRPN gene deletion of chromosome 15q11-13. Bisulfite-modified DNA from all PWS children amplified with methylated allele-specific primer pair showed only maternal 131bp PCR product, indicating the maternal uniparental disomy (UPD15). CONCLUSION: Genomic imprinting plays an important role in the molecular pathogenesis of PWS that caused by paternal microdeletions of 15q11-q13 or maternal UPD of chromosome 15. The basic defect seemed to be an absence of function of PWS genes that are normally expressed only from the paternal chromosome 15. MSPCR is a rapid and simple PCR-based assay compared with other cyto-molecular tests and its results were consistent with the clinical diagnosis of PWS, so it seems to be a reliable diagnostic method for PWS patients who show abnormal methylation at SNRPN. The genetic differential tests for PWS are important in determining familial recurrence risk.

Adolescent↗
PubMed2004

Williams-Beuren syndrome in the Hong Kong Chinese population: retrospective study.

OBJECTIVE: To estimate the incidence and document the clinical characteristics of Williams-Beuren syndrome in the Hong Kong Chinese population. DESIGN: Cytogenetic analysis and retrospective study. SETTING: Clinical Genetic Service, Department of Health, Hong Kong. PATIENTS: Forty-one Chinese patients with Williams-Beuren syndrome. MAIN OUTCOME MEASURES: From 1 January 1995 to 30 June 2002, fluorescence in situ hybridisation was used to confirm diagnoses in 41 cases of Williams-Beuren syndrome by detecting chromosome 7q microdeletion. Case records were reviewed, the incidence of the condition in the local population was estimated, and the main clinical characteristics were determined. RESULTS: The minimal incidence of Williams-Beuren syndrome in this locality was estimated to be approximately 1 per 23500 live births. Common dysmorphic facial features included periorbital fullness (83%), full lips (80%), a long philtrum (51%), a flat nasal bridge (41%), and abnormal teeth (37%). No patients had a stellate iris. The majority (82%) had at least one documented cardiac anomaly; among these patients, peripheral pulmonary stenosis was diagnosed in 61% and supravalvular aortic stenosis in 45%. Nearly all (93%) of the study group exhibited developmental delay. CONCLUSION: As in the West, patients with Williams-Beuren syndrome in the Hong Kong Chinese population display craniofacial dysmorphism, cardiovascular anomalies, and mental deficiency. Supravalvular aortic stenosis-the cardiac defect most commonly associated with Williams-Beuren syndrome in western countries-is less common than peripheral pulmonary stenosis in this region. Studies involving periodic cardiovascular evaluation are needed to confirm if this difference is significant.

Adolescent↗
PubMed2004

Unexpected death of a 12 year old boy with monosomy 1p36.

Monosomy 1p36 may result in a clinically recognizable chromosomal microdeletion syndrome. We report the unexpected death of a 12 year old boy with mildly dysmorphic facial features, short stature at 138 cm (3rd centile), moderate mental retardation and a history of seizures, obesity, transient muscle weakness of the right arm and leg and episodes of transient atonic hemiparesis of the right side of the body. Despite the relatively few congenital anomalies and normal karyotype, the 1p36 deletion was suspected on clinical grounds and was demonstrated by fluorescent in situ hybridisation (FISH). Two months after diagnosis and following a short history of a mild upper airway infection, high fever and severe diarrhea, the patient had a massive circulatory shock and asystolia, resulting in deep coma, brain edema, apallic syndrome and death. To our knowledge there has been no previous report of episodes of transient unilateral muscle weakness and atonic hemiparesis, circulatory shock and sudden death associated with monosomy 1p36.

Alopecia↗
PubMed2004

Focal segmental glomerulosclerosis in solitary kidney in WAGR syndrome.

WAGR syndrome consists of Wilms' tumour, aniridia, genitourinary malformations and mental retardation, and is associated with chromosomal microdeletion of 11p13. We report a case of young male, exhibiting several typical features of WAGR syndrome (e.g. WT, aniridia and genitourinary abnormalities), but missing some other (mental retardation and chromosomal abnormality absent). Renal biopsy performed in our patient for unexplained proteinuria showed focal segmental glomerulosclerosis, presumably of secondary origin; the decrease of proteinuria was achieved by the firm control of BP in conjunction with the reduction of body weight.

Adult↗
PubMed2004

Clinical features of NSD1-positive Sotos syndrome.

It is 40 years since the first case of Sotos syndrome was reported. For most of the past four decades the diagnosis of Sotos syndrome has been dependent on the subjective evaluation of clinical criteria, primarily whether the facial gestalt is present. The recent identification of NSD1 (Nuclear receptor-binding SET domain containing protein) mutations and deletions in the great majority of Sotos syndrome cases has allowed re-evaluation of defining and associated features of the condition. In this review we will present the clinical features of Sotos syndrome cases with proven abnormalities in NSD1. This has allowed redefinition of Sotos syndrome as a condition characterised by a typical facial gestalt, macrocephaly and learning difficulties. Childhood overgrowth, advanced bone age, cardiac and genitourinary anomalies, neonatal jaundice, neonatal hypotonia, seizures and scoliosis are all fairly common in children with Sotos syndrome. A mutation or microdeletion of NSD1 is diagnostic of Sotos syndrome.

Adult↗
PubMed2004

[Idiopathic male infertility and partial copy deletion of DAZ gene family].

OBJECTIVE: To analyze the pattern and prevalence of partial copy deletion of deleted-in-azoospermia (DAZ) gene in the azoospermia factor C(AZFc) region of patients with idiopathic azoospermia or severe oligozoospermia. METHODS: sY581 and sY587 in DAZ gene region were analyzed by polymerase chain reaction-restriction length polymorphism(PCR-RFLP) for its deletion in 197 patients with azoospermia, 166 patients with severe oligozoospermia, and 210 fertile men as controls. RESULTS: Deletion of both DAZ1 and DAZ2 was detected in 18 patients with azoospermia and 10 with severe oligozoospermia, and the prevalence was 9.1% and 6.0% respectively. There was significant difference in deletion rate between the cases and controls. CONCLUSION: The frequency of partial copy deletion of DAZ gene in Chinese idiopathic azoospermia or severe oligozoospermia patients is much higher than that of fertile controls, suggesting that the deletion of DAZ1/DAZ2 may be one of the important genetic etiological factors of spermatogenesis damage. The pattern and prevalence of DAZ partial copy deletion are similar to those of Caucasians populations, and detection of DAZ gene partial copy deletion by PCR-RFLP may be adopted as an additional clinical gene diagnostic measure after AZF microdeletion detection.

Azoospermia↗
PubMed2004

Rubinstein-Taybi syndrome (broad thumb-hallux syndrome).

Rubinstein-Taybi syndrome is a rare genodermatosis with characteristic features that include downward sloping palphebral fissures, broad thumbs and halluces, and mental retardation. Dermatologic manifestations include capillary malformations, keloid formation, and pilomatricomas. Systemic features may involve the cardiac, audiologic, ophthalmologic, endocrine, neurologic, and respiratory systems. The syndrome is sporadic in nature and has been linked to microdeletion at 16p13.3 encoding CREB-binding protein gene (CREBBP).

Child, Preschool↗
PubMed2005

Further delineation of the 22q13 deletion syndrome.

A chromosomal deletion syndrome associated with a 22q13 microdeletion has previously been reported in approximately 75 children. We report six cases from Denmark with a deletion of 22q13. One was cytogenetically visible by conventional karyotyping, one was diagnosed by high resolution karyotyping after the demonstration of low arylsulfatase A activity. Two were diagnosed by high resolution CGH analysis, one was diagnosed by multisubtelomeric FISH analysis and one was diagnosed serendipitously as lack of the control signal in a FISH analysis for 22q11 deletion. One of the cases was a mosaic with 16% of cells showing two signals. The phenotype of the children included: generalized developmental delay, compromised language development, hypotonia, normal or accelerated growth and minor facial dysmorphism. Other features were partial agenesis of the corpus callosum, bilateral ureteropelvic stricture, gastroesophageal reflux and hearing loss. One case had a different phenotype, and showed a deletion as well as a duplication. The extent of the deletion was studied by quantitative PCR analysis of a number of DNA markers in the 22q13 region. The deletions varied in size, extending from 4.0 to 9.0 Mb. The clinical phenotype seemed rather similar although some specific features might be attributable to differences in deletions.

Abnormalities, Multiple↗
PubMed2005

Autosomal dominant inheritance of Williams-Beuren syndrome in a father and son with haploinsufficiency for FKBP6.

Williams-Beuren syndrome (WBS) is a neurodevelopmental microdeletion disorder that usually occurs sporadically due to its location within a highly repetitive genomic region that is unstable and prone to unequal cross-over during meiosis. The consequential loss of chromosomal material includes approximately 1.5 Mb of DNA at 7q11.23. Whilst cases of dominant inheritance have been described in the literature, there have been few reports of molecular confirmation and none have carried out detailed genotyping. We describe a Bulgarian father and son with WBS detected by fluorescent in situ hybridisation (with an elastin gene probe) and loss of heterozygosity mapping using microsatellite markers located in the critical region. These individuals appear to have a common WBS heterozygous deletion, confirming the expected dominant transmission and adding to the few familial cases reported. The deletion includes the gene FKBP6 which has recently been shown to play a role in homologous chromosome pairing in meiosis and male fertility in mouse models. Homozygous Fkbp6 -/- male mice are infertile and our data suggests that haploinsufficiency for FKBP6 does not appear to preclude male fertility in WBS, although male infertility involving this gene has the potential to follow the mouse model as a human autosomal recessive condition.

Adult↗
PubMed2005

[Molecular genetic study of causes of the Prader-Willi and Angelman syndrome].

BACKGROUND: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinctive diseases with severe impairment of psychomotoric development and behaviour. Both syndromes are caused by the loss of paternal (PWS) or maternal (AS) gene expression of chromosomal region 15q11-13. The work reveals the various causes of this loss. The choice of the most suitable method for screening of the genome mutations in the patients suspected of PWS and AS is another purpose of the work. METHODS AND RESULTS: The methyl specific analysis (MS PCR) in locus SNRPN, short tandem repeat (STR) analysis and fluorescent in situ hybridization (FISH) were used. In the group of 55 patients tested for PWS and AS only maternal allele was present in 11 patients and only paternal allele was present in 1 patient in the locus SNRPN: 10 microdeletions 15q11-13, 1 UPD(15)mat and 1 UPD(15)pat. CONCLUSIONS: MS PCR seems to be the most profitable method for the first step of selection of PWS patients. In positive cases is inevitable to use also additional tests of molecular diagnosis to distinguish the particular mechanism leading to the disorders. In AS patients is also MSPCR recommended as the first step although it is necessary to exclude mutation in UBE3A gene in case of MS PCR negativity.

Adolescent↗
PubMed2005

Sperm retrieval for intra-cytoplasmic sperm injection in non-obstructive azoospermia.

Surgical testicular sperm retrieval for intra-cytoplasmic sperm injection (ICSI) purposes is the only possibility of biological fathering in case of non-obstructive azoospermia (NOA). Successful retrieval only correlates with histology, not with FSH values or testicular volume. Concurrent AZFa and AZFb microdeletion predict unsuccessful recovery. Testicular sperm extraction (TESE) (mean of successful retrievals in literature: 52.7%) is the technique of choice: we had successful retrievals in 100% of cases of hypospermatogenesis with > 5 spermatids/tubule (spd/tub), 81.8% of cases of hypospermatogenesis with < 4 spd/tub, 50% of cases of maturation arrest, and 25% of cases of histologically pure Sertoli cell-only syndrome. Microsurgical TESE (mTESE) has been reported to increase successful retrievals: from 16.7-45% for standard TESE to 42.9-63.6% for mTESE, depending on the distribution of testicular histology in the various case studies; from 9 to 14 cases out of 22, respectively, in the only study in which TESE and mTESE were performed simultaneously on the same testis. Improvements in biological procedures for TESE retrievals can increase positive findings. TeFNA does not appear to be indicated in NOA, both because of its low success rates--which, in practice, are only positive in hypospermatogenesis--and because it is unable to detect any carcinomas in situ. Previous surgery of left varicocele in NOA could increase the chances of subsequent recovery. ICSI from TESE has lower birth rates in NOA than in obstructive azoospermia (OA) (19% vs 28%). Abortion rates are significantly higher following ICSI from NOA (11.5%) than from OA (2.5%) (P=0.001). Therefore, the prognostic fertility of a couple with an NOA male is quite lower than for a couple with an OA male.

Humans↗
PubMed2005

Chromosomal studies in infertile men with oligozoospermia & non-obstructive azoospermia.

BACKGROUND & OBJECTIVE: Chromosomal anomalies have been postulated to be as one of the principal genetic factors in male infertility. Cytogenetic evaluation of men with severely compromised semen parameters reveals an increased incidence of chromosomal aberrations when compared with the normal population. The objective of this study was to determine the chromosomal constitution and sperm characteristics among Indian males with severe male factor infertility. METHODS: In this prospective study we investigated 88 infertile men (42 men with azoospermia and 46 men with sperm count <5 x 10(6) million/ml) prior to intracytoplasmic sperm injection (ICSI) treatment. Karyoptying was performed on peripheral blood lymphocytes according to standard methods. Polymerase chain reaction (PCR) was performed to screen the microdeletions in the AZF region of the Y chromosome. RESULTS: Constitutional chromosome abnormalities were identified in 14.3 per cent of azoospermic and 6.5 per cent of oligozoospermic men, with an overall rate of 10.2 per cent. Chromosomal abnormalities included gonosomal aberrations in 5 cases. Robertsonian translocation in one, trisomy 7 mosaicism in one case, deletion in chromosome 16 in one, and a marker chromosome in one case. Chromosome variants were observed in 33 (37.5%) subjects. Yqh- was the most frequent variant in sex chromosomes and increased length in heterochromatin and satellites were observed in autosomal chromosomes. INTERPRETATION & CONCLUSION: The high rate of chromosomal anomalies among infertile men strongly suggests the need for routine cytogenetic analysis prior to employment of assisted reproduction techniques. In addition, meticulous follow-up of babies born after ICSI, especially male offsprings, is necessary.

Adult↗
PubMed2005

Polydactyly in a boy with Smith-Magenis syndrome.

Smith-Magenis syndrome is a microdeletion syndrome involving chromosome 17p11.2. The characteristic features include mental retardation, dysmorphic facial features, minor skeletal anomalies including brachydactyly and behavioural abnormalities, such as disturbed sleep pattern, restlessness and self-destructive behaviour. We present a patient with this syndrome and with six digits on each hand. Polydactyly has not yet been described in Smith-Magenis syndrome as far as we know.

Abnormalities, Multiple↗