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PubMed1996

The Williams syndrome: an Italian collaborative study.

Williams syndrome (WS) is a multiple congenital anomalies/mental retardation syndrome caused by a microdeletion on the long arm of chromoome 7 including the elastin gene. Possibly it is a contiguous gene syndrome with autosomal dominant transmission. Seventy-seven WS patients from 11 Italian Pediatric-Dysmorphology-Genetics Units were collected by means of a questionnaire designed to draw a comprehensive clinical picture, to define the frequency of different traits and associations thereof, to better understand the clinical evolution, to improve the prognosis and to ameliorate the follow-up. The most important signs for diagnosis, based on their relative frequencies, are: mental retardation with characteristic outgoing behaviour and hoarse voice; facial findings like stellate iris, periorbital fullness and thick lips; congenital heart disease. The frequency of the clinical signs reported in our patients are on the whole concordant with those found in the literature; the only significant differences concern low stature, hallus valgus, hypoplastic nails, joint contractures and ear infections. The multisystemic nature of this syndrome requires a coordinated and integrated approach in order to avoid fragmentary interventions.

Abnormalities, Multiple↗
PubMed1997

Molecular pathology of primary and metastatic ductal pancreatic lesions: analyses of mutations and expression of the p53, mdm-2, and p21/WAF-1 genes in sporadic and familial lesions.

BACKGROUND: The molecular pathology underlying the development and progression of ductal pancreatic adenocarcinoma is poorly understood relative to that of other major cancers in industrialized societies. The frequency, nature, and distribution of p53 abnormalities, their temporal relationship to the metastatic and clinicopathologic phenotypes of sporadic and familial pancreatic cancer, and their consequent effects on the genetics and expression of critical wild-type p53-regulated genes (mdm-2 and p21/WAF-1) warrant examination in pancreatic adenocarcinoma. This molecular and immunochemical study of the p53, mdm-2, and p21/ WAF-1 genes and gene products examined the largest series of nonneoplastic, neoplastic, and metastatic ductal pancreatic lesions reported to date in relation to clinicopathologic profile. METHODS: Histologically confirmed specimens of primary (n = 136) and metastatic (n = 23) sporadic and familial ductal pancreatic adenocarcinoma lesions were subjected to immunochemical analyses of p53 expression in which a panel of 3 antibodies was utilized. A panel of nonneoplastic but histologically abnormal pancreatic lesions (n = 77) from individuals with varied histories of cigarette smoking were subjected to similar immunohistochemical examinations. In addition, 3 specimens from patients with chronic pancreatitis, 2 specimens of normal fetal pancreata, and 16 specimens of normal adult pancreata were examined as control tissues. Suitable frozen and archival microdissected tumor lesions were evaluated for mutations in exons 4-9 of the p53 gene by single strand conformation polymorphism (SSCP) and dideoxy sequencing analyses in which two distinct sets of outer and nested intron-based amplification primers were used for each exon. A subset of 25 tumor specimens and 18 tumor-derived cell lines for which the p53 mutation status was known were examined for amplification and/or overexpression of the mdm-2 gene; amplification was determined by Southern hybridization and overexpression by immunohistochemical and Western blot analyses. Similarly, mutations in the coding region of p21/WAF-1 gene were examined by SSCP and DNA sequence analyses, and steady-state expression of the p21/WAF-1 protein was assessed by Western blot analysis in these subsets of tumors and tumor-derived cell lines. RESULTS: Positive ductal nuclear p53 immunostaining was demonstrated in 56% of primary tumors and 54% of metastatic lesions. The frequency did not differ significantly between sporadic and familial lesions, and immunostaining was not observed in ductal, acinar, or islet cell elements of normal pancreata or histologically abnormal benign pancreatic lesions from cigarette smokers. A total of 70% of tumor samples revealed reproducible SSCP abnormalities for p53; 42% of these were found in exons 7 and 8. DNA sequence analysis of cases with greater than 35% epithelial cellularity (n = 25) revealed 17 missense mutations, 12 of which were transitions. Seventy-five percent of these transitions were of G:C-->A:T type. A total of 22% of the p53 mutations identified were microdeletions, along with one insertional mutation at exon 8. None of the normal pancreata from sporadic or familial lesions revealed germ-line p53 alterations. Moreover, the frequency and spectra of p53 alterations exhibited no clear, statistically significant association with tumor grade, TNM stage, or patients' cigarette-smoking histories. The mdm-2 gene was neither amplified nor overexpressed immunochemically in a subset of ductal adenocarcinomas, and there was no clear relationship between the p53 mutation status and the status of the mdm-2 gene or protein. Similarly, SSCP and DNA sequence analysis of the p21/WAF-1 gene revealed only 2 genetic abnormalities in a series of 25 primary tumors and 15 tumor-derived cell lines; 1 of the cell lines also revealed the absence of immunoreactive p21/WAF-1 protein...

Adult↗
PubMed1997

Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome patients with an imprinting mutation.

Recent studies have identified a new class of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients who have biparental inheritance, but neither the typical deletion nor uniparental disomy (UPD) or translocation. However, these patients have uniparental DNA methylation throughout 15q11-q13, and thus appear to have a mutation in the imprinting process for this region. Here we describe detailed clinical findings of five AS imprinting mutation patients (three families) and two PWS imprinting mutation patients (one new family). All these patients have essentially the classical clinical phenotype for the respective syndrome, except that the incidence of microcephaly is lower in imprinting mutation AS patients than in deletion AS patients. Furthermore, imprinting mutation AS and PWS patients do not typically have hypopigmentation, which is commonly found in patients with the usual large deletion. Molecular diagnosis of these cases is initially achieved by DNA methylation analyses of the DN34/ZNF127, PW71 (D15S63), and SNRPN loci. The latter two probes have clear advantages in the simple molecular diagnostic analysis of PWS and AS patients with an imprinting mutation, as has been found for typical deletion or UPD PWS and AS cases. With the recent finding of inherited microdeletions in PWS and AS imprinting mutation families, our studies define a new class of these two syndromes. The clinical and molecular identification of these PWS and AS patients has important genetic counseling consequences.

Adult↗
PubMed1996

[Neurologic diseases and chromosome 17].

On the short arm of the 17th chromosome is a peripheral myelin protein (PMP22) the duplication or point mutation of which causes the development of some congenital autosomal dominant hereditary demyelinization neuropathies: the most frequent variants of Charcot-Marie-Tooth disease (CMT1A), some cases of Déjérine-Sottas disease and microdeletion of PMP22 and hereditary pressure neuropathies. The pericentric section of the long arm of chromosome 17 comprises a locus conditioning the development of the most frequent phacomatosis-neurofibromatosis 1. As to rarer neuromuscular diseases, genome mutations of chromosome 17 condition the development of some cases of autosomal recessive forms of severe muscular dystrophy (SCARMD), a clinical analogue of Duchenne's form of muscular dystrophy, metabolic storage myopathy of Pompe's type and some muscle diseases associated with impaired function of the ion channels (hyperkalaemic periodic paralysis, congenital paramyotonia, some cases of malignant hyperthermia). Aspartoacylase deficiency, conditioning Canavan's leucodystrophy was also located in the area of the short arm of chromosome 17.

Chromosomes, Human, Pair 17↗
PubMed1996

[Neurocristopathies and chromosome 22 deletions].

Microdeletions of 22q11.2 are associated with a wide range of congenital disorders involving structures derived from the third and fourth pharyngeal pouches. This observation suggests that one major gene playing a part in rhombencephalic neural crest cells migration is localized in this small genomic region. Seven new genes have already been mapped to this detected region. Even if there is no clear evidence for the involvement of one of these genes in the pathogenesis of the disorder, these new molecular data provide us with a very efficient diagnosis tool.

Chromosome Deletion↗
PubMed1997

Nasal dimple as part of the 22q11.2 deletion syndrome.

The phenotype of the 22q11.2 microdeletion syndrome is quite variable. We describe 2 patients with a 22q11.2 deletion and a dimpled nasal tip, which, we suggest can be the extreme of the broad or bulbous nose commonly found in the 22q11.2 deletion syndrome, and should not be confused with the more severe nasal abnormalities seen in frontonasal dysplasia.

Chromosome Deletion↗
PubMed1997

The brain finger protein gene (ZNF179), a member of the RING finger family, maps within the Smith-Magenis syndrome region at 17p11.2.

Smith-Magenis syndrome (SMS) is caused by a microdeletion of 17p11.2 and comprises developmental and growth delay, facial abnormalities, unusual behavior and sleep problems. This phenotype may be due to haploinsufficiency of several contiguous genes. The human brain finger protein gene (ZNF179), a member of the RING finger protein family, has been isolated and mapped to 17p11.2. FISH analyses of metaphase or interphase chromosomes of 6 patients with SMS show that ZNF179 was deleted in one of the 2 homologs (17p11.2), indicating a possible association of the defect of this gene with the pathogenesis of SMS. Furthermore, using a prophase FISH ordering system, we sublocalized ZNF179 proximally to LLGL which lies on the critical region for SMS.

Abnormalities, Multiple↗
PubMed1997

Pilot studies for proficiency testing using fluorescence in situ hybridization with chromosome-specific DNA probes: a College of American Pathologists/American College of Medical Genetics Program.

Fluorescence in situ hybridization using chromosome-specific DNA probes is rapidly becoming part of clinical laboratory practice for certain congenital and neoplastic disorders. Current legislation requires proficiency testing for clinical laboratory studies. To evaluate the efficacy of fluorescence in situ hybridization proficiency testing, we invited 19 representative institutions to participate in three pilot studies. One study used probes for the X and Y chromosomes to evaluate metaphase spreads and interphase nuclei. Another study used probes for bcr and abl to detect bcr/abl fusion in interphase nuclei in chronic myelogenous leukemia. The third study used a D22S75 probe to detect microdeletions in metaphase spreads from a patient with velocardiofacial syndrome. The results of these studies demonstrate that proficiency testing with fluorescence in situ hybridization is attainable using either metaphase or interphase preparations, and that either microscope slides or fixed cell pellets are suitable.

Chromosome Mapping↗
PubMed1997

CATCH 22: deletion of locus 22q11 in velocardiofacial syndrome, DiGeorge anomaly, and nonsyndromic conotruncal defects.

DiGeorge anomaly (DGA) and velocardiofacial syndrome (VCFS) are frequently associated with monosomy of chromosomal subband 22q11. It is not clear whether individuals who present with only some of the features (e.g., isolated hypoparathyroidism or conotruncal defects) of these conditions also have the same deletion. In a prospective study of 30 children from 1994 to 1996, we used both high-resolution banding and fluorescence in situ hybridization (FISH) to assess the deletion status of children with a wide range of DGA-like or VCFS-like clinical features. Microdeletion of the chromosomal subband 22q11.22 was detected in 17 children by high-resolution banding and in two additional children with conotruncal defect (CTD) who had submicroscopic deletions proved by FISH analyses. Of the patients with microscopical deletion (n = 17), only six had classical DGA (n = 4) or VCFS (n = 2) phenotypes. The other 11 had various forms of congenital heart defects as the only presenting signs of deletion. One patient with DGA stigmata had another chromosomal aberration of monosomy 10p13. Only 10 patients were found to have neither cytogenetic nor molecular abnormalities. Therefore, it appeared that the majority, if not all, of the DGA and VCFS patients with the 22q11 deletion were identifiable using FISH with the single N25 (D22S75) probe. It would also be advisable that children with isolated CTD should be carefully examined to detect the other morphologic abnormalities of DGA and VCFS, or CATCH 22 (cardiac defects, abnormal facies, thymic hypoplasia/aplasia, cleft palate, hypocalcemia, and 22q11 deletion). Once these abnormalities are found, a molecular cytogenetic analysis for the so-called 22q11 region is indicated. Because of other associated chromosomal findings, routine or high-resolution cytogenetic analysis should be performed on patients with suspected CATCH 22.

Abnormalities, Multiple↗
PubMed1997

[Genetic diagnosis of Williams syndrome].

Williams syndrome is a complex developmental disorder. The major cardiovascular component of Williams syndrome is supravalvular aortic stenosis, a progressive disease that may need surgical repair. Williams syndrome is associated with heterozygous microdeletion in the chromosomal region 7q11.23 encompassing the elastin gene. We have identified a new, highly informative tetranucleotide repeat polymorphism within the human elastin gene. This marker together with other, previously described elastin gene markers was used to show deletion of the elastin gene in nine sporadic Williams syndrome patients from Hungary. Application of polymorphisms within and flanking the elastin gene on chromosome 7 provides a fast, polymerase chain reaction based method for mutational analysis of Williams syndrome patients.

Aortic Valve Stenosis↗
PubMed1997

[Familial supravalvular aortic stenosis. Investigation in a family and review of the literature].

Familial supravalvular aortic stenosis is a rare autosomal dominant condition. It may be distinguished from the Williams-Beuren syndrome by the absence of the characteristic dysmorphic appearances and of mental retardation. The case of a 9-year-old girl with a severe surgical stenosis led to the diagnosis of the same malformation in the mother and two brothers. This family adds to the 121 cases reported in the literature describing the main features of SVAS. Molecular biological advances have shown that familial SVAS and the Williams syndrome are due to mutation of the elastin gene located at 7q11-23. In the Williams syndrome the allele of this gene is completely absent and there is also probably deletion of contiguous genes, which explains involvement of cognitive function. In SVAS, the genetic lesion, mutation or microdeletion is more limited, explaining the usually isolated aortic malformation. Other studies are necessary to confirm these results.

Adult↗
PubMed1996

Characterization of a de novo t(Y;9) (q11.2;q22) by FISH technique.

A new case with a de novo translocation involving the long arms of chromosomes Y and 9 i.e. 46, X, t(Y;9) (q11.2;q22) was noted in a phenotypically normal male as revealed by GTG technique and subsequently confirmed using dual color whole chromosome painting probes. Since the Yq11.2 region was involved in the translocation the fecundity status of the individual has been questioned. Previous cases with (Y;autosomal) translocations have produced males with azoospermia, a variety of male gamete deformities and idiopathic sterility. The azoospermic factor (AZF) on the distal Yq11 band, which apparently controls spermatogenesis, may have been adversely affected due to a microdeletion, rearrangement or complete loss as a result of the translocation mechanism. Testicular histological and fertility tests of the proband at a postpubescent age will reveal the status. The sex determining region (SRY) on the Yp, which has been equated with the testis determining factor (TDF), is believed to be intact. Dual color whole chromosome painting probes, which served as an important adjunct to GTG banding, increased the degree of certainty for the characterization of the involved translocation. A concise review of balanced (Y ; autosome) translocation cases are annotated here.

Chromosomes, Human, Pair 9↗
PubMed1997

[Genetic investigation required in male infertility].

Four men aged 38, 31, 27 and 35 years were examined because of infertility. The first three had idiopathic oligozoospermia, the other bilateral ductus deferens agenesis. They were referred for intracytoplasmic sperm injection (ICSI). Clinical genetic investigation including thorough family history, chromosome investigation and molecular DNA investigation revealed that one patient had mosaicism for Klinefelter syndrome (46,XY/47,XXY), the second a familial balanced translocation (46,XY,t(4;16)) and the third a microdeletion in the AZFc region of the Y chromosome, while the fourth was homozygous for a cystic fibrosis mutation. In view of new fertilisation techniques such as ICSI, clinical genetic investigation is of great importance. It is not known whether these new techniques facilitate transmission of genetic disorders. Long-term follow-up of children conceived by ICSI is required.

Adult↗
PubMed1998

Identification of a large deletion, spanning exons 4 to 11 of the human factor XIIIA gene, in a factor XIII-deficient family.

Inherited deficiency of factor XIIIA subunit (FXIIIA) is an autosomal recessive disorder that is characterized by a life-long bleeding tendency and complications in wound healing. Molecular genetic studies have shown the deficiency can be due to small sequence changes within the FXIIIA gene, such as point mutations or microdeletions. On molecular analysis of the FXIIIA gene in an FXIII-deficient patient, of United Kingdom origin, we identified a putative homozygous missense mutation, Arg408Gln. However, the father of this patient is homozygous normal for arginine at codon 408. Having proved paternity in this pedigree by microsatellite analysis, we examined the FXIIIA RNA of the patient by reverse transcriptase-polymerase chain reaction and found the paternal allele to lack exons 4 through 11 inclusive. Hence, a huge deletion extending from intron 3 to intron 11 and the Arg408Gln mutation are jointly responsible for FXIIIA deficiency in this family. This is the first finding of such a large deletion in the FXIIIA gene.

Adult↗
PubMed1998

Molecular delineation of 13q deletion boundaries in 20 patients with myeloid malignancies.

Fluorescent in situ hybridization (FISH) analysis with a panel of DNA probes for 13q13.1-q14.3 was performed on 20 cases of myeloid malignancies, of which 17 showed a del(13)(q) and three had translocations affecting 13q. By chromosome morphology, deletions consistently involved bands q14 and q21. In addition to confirming the chromosome data, FISH allowed us to delineate a commonly deleted region that was flanked by YAC 833A2 and YAC 854D4. Three cases with 13q translocations unexpectedly showed accompanying cryptic microdeletions of 13q, and in one case the commonly deleted region could be narrowed to a genomic segment, which includes YAC 937C7, RB1, and YAC 745E3. Homozygous deletions were not detected. This region overlaps with the smallest deleted region of 13q14 in chronic lymphocytic leukemia.

Adult↗
PubMed1997

Molecular medicine: a primer for clinicians Part. XI: Clinical implications of the new genetics-II.

This installment in the series complements Molecular Medicine X to complete the discussion of "non-traditional inheritance"-concepts recently recognized or expanded to explain clinical observations that do not fall neatly under mendelian laws. These include mosaicism, genomic imprinting, uniparental disomy, triplet repeats, microdeletions and contiguous gene syndromes, and mitochondrial disorders.

DNA, Mitochondrial↗
PubMed1998

Deletion of 22q11 in two brothers with different phenotype.

We have studied two brothers with submicroscopic 22q11 deletion. One brother had findings suggestive of DiGeorge syndrome, while the other had milder anomalies, including polydactyly. Fluorescence in situ hybridization (FISH) showed a minor cell line with deletion 22q11 in the mother. To our knowledge, this is the first report of a deletion of 22q11 in two sibs with different phenotypes and apparent maternal mosaicism detected with FISH. This family illustrates the variability of the syndrome and further demonstrates the possibility of gonadal mosaicism for a microdeletion. Prenatal diagnosis may be offered after the birth of a child with a 22q11 deletion, even in the absence of parental chromosomal anomalies.

Child↗
PubMed1998

Strong variable clinical presentation in 3 patients with 7q terminal deletion.

We report 3 patients with a 7q terminal deletion. The first, a 7 weeks old female, with a de novo 7q36-->qter deletion, was microcephalic and had a partial hypoplasia of the corpus callosum on the MRI-scan of the brain. The second, a 3 months old male, showed microcephaly, disproportionate growth retardation, truncal obesity and facial dysmorfism giving the clinical impression of a "microcephalic primordial dwarfism (osteodysplastic type)". At the age of 6 months he had developed a single maxillary central incisor suggesting a minimal form of holoprosencephaly (HPE). Additional FISH-studies showed a 7q36.1-->qter deletion, as the unbalanced product of a t(5;7)(q35.2;q36.1)pat. The de novo 7q36-->qter deletion in the third patient, a 5 years old female, was associated with borderline intelligence, mild microcephaly, small midface, choanal narrowing and a single maxillary central incisor as a minimal form of HPE. CT- and MRI-scan of the brain were normal. In these 3 patients extensive FISH analysis was performed to investigate the possible involvement of the HPE gene region on chromosome 7q36. The target gene for HPE, the Sonic hedgehog gene (SHH) as well as several other genes important for normal brain development (En2;HOX1,HTR5A) were found to be deleted in all three patients. Our findings stress the importance of 7q36 microdeletion studies in patients with even minimal signs of HPE, as relative microcephaly with small midface (choanal narrowing), agenesis/hypoplasia of the corpus callosum/septum pellucidum, thalamic fusion or a single maxillary central incisor.

Abnormalities, Multiple↗