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Biomedical subjects

C Sultan

Publications and source records attributed to C Sultan.

At least 73 records · Page 4Linked to original sources
PubMed1993

Androgen receptor gene mutation in male breast cancer.

We screened thirteen male breast cancers for the presence of germline mutations in exons 2 and 3 encoding the DNA-binding domain of the androgen receptor. These two exons were amplified from genomic DNA extracted from patients' white blood cells. In one of these thirteen patients, single strand conformation polymorphism and direct sequencing detected a guanine-adenine point mutation at nucleotide 2185 that changes Arg608 into Lys in a highly conserved region of the second zinc finger of the androgen receptor. This mutation occurred in a 38 year old man with partial androgen insensitivity syndrome and normal androgen-binding capacity in cultured genital skin fibroblasts. To our knowledge, only one germline Arg to Gln androgen receptor gene mutation has been previously reported at position 607 in male breast cancer. This androgen receptor mutation along with the Arg608 into Lys mutation we describe, suggests that this genetic abnormality is not fortuitous: a decrease in androgen action within the breast cells could account for the development of male breast cancer by the loss of a protective effect of androgens on these cells. Activation of estrogen regulated genes by the change of DNA-binding characteristics of the mutant androgen receptor cannot, however, be ruled out.

Adult↗
PubMed1993

Increased oestradiol level in seminal plasma in infertile men.

Seminal hormonal patterns in fertile and infertile men were investigated. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, testosterone and oestradiol were assessed by radioimmunoassay, and dehydroepiandrosterone sulphate (DHAS) by bioluminescence assay, on blood and seminal plasma of 23 fertile men and 83 infertile men. For fertile men, mean FSH, LH, testosterone and DHAS concentrations were lower and mean oestradiol was higher in seminal than in blood plasma; prolactin did not differ. For infertile men, mean seminal FSH and LH showed a moderate but significant increase compared with fertile men; testosterone, DHAS and prolactin did not differ but mean seminal oestradiol was significantly increased. Of the infertile men, 53% had seminal oestradiol concentration above the 90th percentile value for fertile men. The meaning of this seminal oestradiol increase is unclear since it is not known whether it is the cause or the consequence of the alteration of spermatogenesis in infertile men. Further studies are required to explore the possible therapeutic implications.

Dehydroepiandrosterone↗
PubMed1993

PCR analysis and sequencing of the SRY sex determining gene in four patients with bilateral congenital anorchia.

OBJECTIVE: We explored the possibility of a genetic anomaly in the sex determining region of the Y chromosome, SRY gene, known to be equated to the testis determining region. PATIENTS: Four patients with bilateral congenital anorchia, absence of testicular tissue, elevated FSH and a lack of testosterone response to human chorionic gonadotrophin stimulation tests were studied. MEASUREMENTS: Amplification by polymerase chain reaction of the SRY gene and direct double stranded DNA sequencing were performed with the same primers. RESULTS: The expected 648 basepairs band of SRY was detected in the four DNA samples from patients with bilateral congenital anorchia. Direct sequencing did not show any difference with the previous published sequence. CONCLUSIONS: These data suggest that, in the four patients, bilateral congenital anorchia is not related to an anomaly of the opening reading frame sequence of the SRY gene.

Child, Preschool↗
PubMed1993

[Familial form of partial androgen insensitivity (Reifenstein syndrome): arginine-histidine mutation in position 840 in the androgen receptor].

In a large kindred with Reifenstein syndrome, we performed the molecular analysis of the androgen receptor gene. Since the biochemical characteristics of the androgen receptor, determined on the cultured genital skin fibroblasts, showed a drastic decrease of the androgen binding capacity, we assumed that a point mutation was located in exons 4-8 encoding the carboxy-terminal domain of the receptor. Enzymatic amplifications of these exons did not point out any deletions. Direct sequencing showed a G-A point mutation at position 2818 of exon 7 responsible for an arginine-histidine substitution at position 840 of the androgen receptor. The presence of the same mutation has been reported by other groups in four unrelated patients. Its association with different phenotypes of androgen insensitivity and different biochemical characteristics of the androgen receptor pointed out the complexity of the genotype-phenotype relationship in androgen insensitivity. Moreover the identification of the point mutation gave us the opportunity to perform a prenatal exclusion diagnosis of Reifenstein syndrome in this high-risk family.

Arginine↗
PubMed1993

[Klinefelter syndrome in 1993. Results of a multicenter study on 58 cases and review of the literature].

A retrospective multicenter study found 58 cases of Klinefelter syndrome of which 23 (39%) were diagnosed before puberty. Although as common as Down syndrome, Klinefelter syndrome is underdiagnosed and often recognized only in adulthood. Suggestive manifestations in infants, children, and teenagers include facial dysmorphism, micropenis, and delayed speech and should lead to examination of the karyotype. Early recognition of Klinefelter syndrome could be achieved by routinely measuring the size of the testes in school-boys aged 11 to 15 years and performing a karyotype in boys with a volume of less than 2 ml. Early psychological and educational support and testosterone replacement therapy initiated at onset of puberty may lead to improved social and academic outcomes.

Adolescent↗
PubMed1992

Myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) with myelofibrosis.

Acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) enter rarely in the differential diagnosis of myelofibrosis (MF). MF of marked intensity, resulting in either "dry taps" or non-representative smears, is encountered in approximately 10% of cases. MF may be observed in any type of AML, most frequently in acute megakaryoblastic leukemia (M7). Apart from some typical cases of MDS, MF is associated with cases of acute myelodysplasia with myelofibrosis (and a major megakaryocytic component). This syndrome has been described under various headings: acute or malignant myelosclerosis, and acute MF. It should be distinguished from M7 and from myeloproliferative syndromes.

Acute Disease↗
PubMed1992

Prenatal prediction of androgen insensitivity syndrome using exon 1 polymorphism of the androgen receptor gene.

Exon 1 polymorphism of the androgen receptor (AR) gene is characterized by a (CAG)n(CAA) repeat at position 172 following the translation start codon. The aim of this study was to determine whether AR gene exon 1 polymorphism could be used to perform prenatal diagnosis in high risk families with complete or partial androgen insensitivity syndrome. After enzymatic amplification of a 1 kilobase exon 1 fragment, each DNA was simultaneously digested by MspI and PstI restriction enzymes. After electrophoresis on a 15% electrophoresis on a 15% acrylamide gel or a 6% Nusieve gel, we measured the size of the obtained fragments and determined the number of CAG repeats since a 282 basepair fragment corresponds to 21 CAG. We previously showed that the number of CAG repeats within the AR gene exon 1 in 23 families with complete or partial androgen insensitivity syndrome was 19 +/- 4. By this method, we detected heterozygosity in 50% of the mothers. We present here 2 exclusion prenatal diagnoses using exon 1 polymorphism of the AR gene. Family A presented a boy with a severe form of partial androgen insensitivity syndrome. The mother had 2 uncles with ambiguous genitalia. In family B, the affected child had a complete androgen insensitivity syndrome. In both families, analysis of the AR gene exon 1 polymorphism of the trophoblastic DNA showed the presence of the normal maternal X chromosome. The parents decided to carry on the gestation. In family A, the newborn had normal male external genitalia. In family B, sonography confirmed the presence of normal male external genitalia. These data suggest that exon 1 polymorphism of the AR gene could be prenatally used to predict androgen insensitivity syndrome.

Androgens↗
PubMed1992

Molecular analysis of the sex-determining region from the Y chromosome in two patients with Frasier syndrome.

In the Frasier syndrome there is an association between XY gonadal dysgenesis and chronic renal failure. Owing to an observed sex reversal, the Y chromosomes of two girls with this syndrome have been analyzed. Using molecular-biology techniques, no major alterations of the known sex-determining area of the Y chromosome were found. Furthermore, the sequence did not reveal impairment of the recently described testis-determining factor SRY. These data suggest that in the Frasier syndrome, XY sex reversal and renal failure could be the result of either faulty gene(s) located downstream in the sex differentiation pathway during embryogenesis, or impaired SRY regulation. Preliminary results on the Wilms' tumor suppressor gene WT1, a candidate for acting downstream to SRY, are also provided.

Adolescent↗
PubMed1992

Molecular biology of disorders of sex differentiation.

Sexual ambiguity can be a difficult and sometimes confusing diagnostic problem in children. Recent developments in molecular biology have provided the opportunity to analyze the gene responsible for testicular determination, SRY, the androgen receptor gene and the gene encoding the cP450 enzyme specific for 21-hydroxylation, CYP21B, whose defects are responsible for congenital adrenal hyperplasia. Southern-blotting studies and PCR analyses of SRY, androgen receptor and CYP21B genes can be routinely used for the direct diagnosis of gonadal dysgenesis, androgen insensitivity syndromes and congenital adrenal hyperplasia, respectively. In sex-reversed XY females, several de novo mutations or deletions in the SRY gene have been reported. Defects in the human androgen receptor cause a spectrum of defects in male phenotypic sexual development associated with abnormalities in the receptor protein. Analyses of the androgen receptor gene structure have identified the causative mutation in some families: mutations that result in large-scale alterations of the structure of the androgen receptor, mRNA or gene mutations that alter the primary structure of the androgen receptor protein and mutations that alter the level of mRNA. The diversity of clinical phenotypes, apparent in 21-hydroxylase deficiency, is paralleled by a considerable degree of mutational heterogeneity in the CYP21 gene locus. Various changes causing severe 21-hydroxylase deficiency have been reported: point mutations, gene conversions and gene deletions. In conclusion, substantial progress has been made elucidating genetic defects causing sex reversal in XY females, the androgen insensitivity syndrome and congenital adrenal hyperplasia. Molecular genetics can also be applied for carrier identification and prenatal diagnosis.

Disorders of Sex Development↗
PubMed1992

Screening for Y-derived sex determining gene SRY in 40 patients with Turner syndrome.

In Turner patients, the presence of a Y chromosome or derivative Y is correlated with the risk of gonadoblastoma induction. "Marker" chromosomes originating from Y, may not show characteristic fluorescence and then be very difficult to identify by conventional cytogenetic techniques, although they still predispose the patients to gonadal tumors. Using polymerase chain reaction of the gene from the sex-determining region of the Y chromosome, we screened 40 Turner patients (thirty seven 45X and three 45X,46XX) for the presence of Y chromosomal DNA. We were able to identify karyotypically unrecognized Y chromosome material in 1 patient out of the 40 studied. In this patient mild clinical and biological hyperandrogenism was observed. Reliability of our technique was ascertained by the detection of the expected 648 base pairs amplified DNA fragment in all normal male controls as well as in 3 Turner patients with confirmed 45X,46XY mosaicism. Despite the low frequency of unrecognized Y chromosome material (1 case over 40 in our experience), our data suggest that polymerase chain reaction of the gene from the sex-determining region of the Y chromosome is worthy of being performed in Turner patients considering the potential risk of the presence of a Y chromosome.

Adolescent↗
PubMed1992

[Normal sexual differentiation: molecular genetic and endocrinology].

Analysis of the sexual determination and differentiation factors has progressed by the important findings made in biochemistry (hormonal assays, determination of the receptor concentration), in cellular and molecular endocrinology (mechanism of the hormonal action) and in genetics (identification, isolation and cloning of the genes implied in the sexual determination and differentiation pathways). We first describe the basis of sexual determination and differentiation, and then we analyze the different roles of SRY gene, encoding for the testis determining factor, androgen receptor gene, 5 alpha-reductase gene and anti-Müllerian hormone gene.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1992

Expert system design in hematology diagnosis.

A two-part study was designed to test the hypothesis that sufficient information is available from a modern hematology analyzer (the Coulter STKS) to reach a reliable intermediate conclusion which can be used as input to the next decision-making level in the design of a high-performance expert system for hematology diagnosis. In phase one, we analyzed the performance of three probabilistic systems (using Bayes' rule) which interpret STKS data: a control system which took the traditional approach of classifying cases into specific diagnoses, and two test systems which were designed to reach only an intermediate conclusion but not a final diagnosis. One of the test systems classified cases into "textbook categories" of disease and the other utilized defined diagnostic patterns. The systems were tested with 150 cases. The pattern approach ranked the correct choice first in 141 of 150 cases (94%). In phase two, we abandoned Bayes' rule, reformulated the pattern approach into a heuristic classification system, and tested its reliability on 820 cases. The algorithm of the reformulated system was able to classify all 820 cases into the same predominant pattern as a panel of three experienced laboratory hematologists.

Algorithms↗
PubMed1991

Involvement of platelet glycoprotein IIb-IIIa (alpha IIb-beta 3 integrin) in thrombin-induced synthesis of phosphatidylinositol 3',4'-bisphosphate.

32P-Labeled human platelets were incubated with thrombin (1 unit/ml) for 5 min at 37 degrees C under conditions allowing maximal synthesis of [32P]phosphatidylinositol 3',4'-bisphosphate (PtdIns(3,4)P2). Incorporation of 32P into the latter phosphoinositide was dose-dependently reduced (to a maximal level averaging 60%) by the tetrapeptide RGDS, an inhibitor of fibrinogen binding to activated glycoprotein IIb-IIIa (alpha IIb-beta 3 integrin). Identical results were obtained with the fibrinogen gamma-chain dodecapeptide HHLGGAKQAGDV, whereas the tripeptide RGD and the tetrapeptide RGES displayed reduced or undetectable effects on 32P labeling of PtdIns(3,4)P2, respectively, in good correlation with their ability to inhibit platelet aggregation and fibrinogen binding to activated alpha IIb-beta 3 integrin. In addition, pathological platelets from three patients suffering thrombasthenia, which lack alpha IIb-beta 3 integrin and fail to aggregate in response to thrombin, displayed hardly detectable increases in the 32P labeling of PtdIns(3,4)P2. In contrast, thrombin-stimulated synthesis of PtdIns(3,4)P2 was unaltered in other deficient platelets lacking the glycoprotein Ib-IX complex (Bernard-Soulier syndrome). Although additional pathways seem to be involved in the regulation of phosphatidylinositol-3-kinase, these data indicate a strong relationship between platelet aggregation involving fibrinogen binding to activated alpha IIb-beta 3 integrin and the synthesis of the novel phosphoinositides phosphorylated at position D-3 of the inositol ring.

Amino Acid Sequence↗