1/13. Progressive dystonia in a child with chromosome 18p deletion, treated with intrathecal baclofen.We report a case of dystonia with a partial deletion of the short arm (p) of chromosome 18 and androgen insensitivity. Neurologic findings in the 18p syndrome are reported to include mental retardation, seizures, incoordination, tremor, and chorea. A 15-year-old girl with a denovo 18p deletion [karyotype 46, XY, del (18)(p11.1)] developed progressive asymmetric dystonia. She had oromotor apraxia and partial expressive aphasia since childhood, and she was able to partially communicate through elementary sign language. At the age of 15 years, she developed subacute and progressive choreic movements of the right arm, severe dystonic posturing of the left arm, and spastic dystonia in both legs. Her response to parenteral or oral benzodiazepines, oral trihexyphenidyl, benztropine mesylate, baclofen, and L-dopa were brief and inadequate. The response to intrathecal baclofen has been sustained over 18 months. In all likelihood, the 18p deletion syndrome affecting this patient is significant in the pathogenesis of her acquired dystonia. Chronic intrathecal baclofen therapy via pump has been effective in this case and should be considered as a treatment modality in carefully selected patients with dystonia.- - - - - - - - - - ranking = 1keywords = androgen (Clic here for more details about this article) |
2/13. Defective sexual development in an infant with 46, XY, der(9)t(8;9)(q23.1;p23)mat.We report on a male infant with ambiguous genitalia (scrotal hypospadias, sinus urogenitalis) trisomic for 8q23-ter and monosomic for 9p23-ter, who shared craniofacial and other abnormalities with either phenotype. Gonadal histology was nearly normal for age. Normal endocrinological findings and exclusion of mutations in SRY, androgen receptor and alpha-reductase genes point to supplementary gene(s) located in 9p2305-ter, haplo-insufficiency (by deletion) of which is expected to cause defective male morphogenesis. CONCLUSION: This observation lends further support to the hypothesis that genetic factors are located at 9p23-ter which are involved in normal sex determination.- - - - - - - - - - ranking = 1keywords = androgen (Clic here for more details about this article) |
3/13. association of polycystic ovary syndrome with an interstitial deletion of the long arm of chromosome 11.Several pathways have been implicated in the etiology of the polycystic ovary syndrome (PCOS). The observation of familial aggregation of PCOS is consistent with a genetic component of this disorder. We report on a 21-year-old woman with menstrual irregularity, hirsutism, elevated serum androgen levels and polycystic ovarian morphology on ultrasonography, meeting the diagnostic criteria of PCOS. A cytogenetic investigation was performed because of a congenital heart defect, craniofacial anomalies in infancy (quadricephaly with protruding forehead, flat nasal bridge, low set ears with attached earlobes, small mouth, high arched palate with submucous palatal cleft, retrognathia), broad neck, motor and speech developmental delay. Chromosomal analysis revealed an unbalanced interstitial deletion of one of the chromosomes 11 [del (11) (q21q23.1)]. Interstitial deletions of the long arm of chromosome 11 have been reported in at least 18 patients. Candidate genes for PCOS have not been suspected at this chromosomal location so far. follistatin and CYP11A, the genes with the strongest evidence for linkage with PCOS, are located on chromosomes 5 and 15. In the chromosomal region deleted in our patient a progesterone receptor gene is located in band q22. Lowered progesterone receptor concentration is associated with retardation of endometrial development. A disturbance of the hypothalamic-pituitary gonadal axis, due to a reduction of hypothalamic and pituitary progesterone receptors might be a component in the etiology of PCOS.- - - - - - - - - - ranking = 1keywords = androgen (Clic here for more details about this article) |
4/13. del(X)(p22.1)/r(X)(p22.1q28) Dynamic mosaicism in a turner syndrome patient.We report on a 16-year-old patient with turner syndrome who presented a mos 46,X,del(X)(p22.1)[35]/45,X [19]/46,X,r(X)(p22.1q28)[6]GTG-band karyotype. The R-banding showed that the abnormal X-chromosome was inactive in all 61 cells analyzed. fluorescence in situ hybridization with a Xp/Yp subtelomeric probe revealed that both abnormal chromosomes lacked the complementary sequences, a fact consistent with a terminal deletion. Besides, the molecular analysis of the human androgen receptor gene showed that the rearranged chromosome was paternal in origin. Since the deleted and the ring chromosomes had the same size and banding pattern, and because the former was the predominant cell line, it was inferred that the Xp- formed a ring in some cells apparently without further loss of genetic material. However, the reverse sequence and even a simultaneous origin due to a complex intrachromosomal exchange are also conceivable. The mild Turner syndrome phenotype is explained by the mosaicism and by the size of the deleted segment.- - - - - - - - - - ranking = 1keywords = androgen (Clic here for more details about this article) |
5/13. Functional disomy for Xq22-q23 in a girl with complex rearrangements of chromosomes 3 and X.A 5-year-old girl with developmental and growth retardation is reported with complex chromosome rearrangements consisting of a partial Xq deletion and an abnormal chromosome 3 with multiple breakpoints. GTG-banding, and multiplex and conventional FISH studies showed that a 6.6-Mb Xq22-q23 segment was inserted into 3q, in addition to three intrachromosomal insertions in chromosome 3. Her karyotype was thus interpreted as 46,X,der(X)(Xpter-->Xq22::Xq23-->Xqter),der(3)(3pter-->3p26::3p12-->3q25.3::3p12- ->3p26::Xq22-->Xq23::3q25.3-->3qter). Replication R-banding study showed that the der(X) was inactivated in all blood lymphocytes analyzed. Methylation-specific PCR at the androgen receptor gene (HUMARA) locus at Xq11-q12 showed a skewed inactivation pattern with the active/inactive x chromosome ratio of 92/8. These data indicated the presence, in the majority of cells, of a functioning Xq22-q23 segment in both the normal X and the der(3) chromosomes. Her growth retardation, developmental delay, and other minor anomalies were most likely caused by dosage effects of the genes in the functionally disomic Xq22-q23 region. Despite the presence of two active copies of the proteolipid protein 1 gene (PLP1), she did not show the symptoms of pelizaeus-merzbacher disease, a subset of which has been known to be caused by the duplication of PLP1.- - - - - - - - - - ranking = 1keywords = androgen (Clic here for more details about this article) |
6/13. Complete androgen insensitivity due to deletion of exon C of the androgen receptor gene highlights the functional importance of the second zinc finger of the androgen receptor in vivo.Androgen-dependent gene transcription is mediated by the androgen receptor (AR) through interaction of its central zinc finger region with specific DNA sequences on target genes. Failure of this receptor-mediated gene transcription results in end organ resistance to androgens-the androgen insensitivity syndromes. In a pair of siblings with complete androgen insensitivity who had supranormal levels of androgen binding in genital skin fibroblasts, polymerase chain reaction and Southern blot analysis of the androgen receptor gene confirmed by polymerase chain reaction and sequence analysis of AR cDNA, revealed an in-frame deletion of exon C encoding the second zinc finger of the receptor. The mutant receptor in cultured genital skin fibroblasts had normal androgen binding affinity and was localized in the nucleus but had markedly reduced DNA-binding affinity. When recreated in vitro and tested in a cotransfection assay system the mutant receptor failed to activate transcription of an androgen-responsive reporter gene. This naturally occurring mutation highlights the functional dependence of the AR upon its second zinc finger in vivo and explains the complete insensitivity to androgen manifest by the affected individuals despite increased androgen binding. The elevated AR levels in the subjects' genital skin fibroblasts further suggests a possible role for the second zinc finger in autoregulation of receptor levels in vivo.- - - - - - - - - - ranking = 22keywords = androgen (Clic here for more details about this article) |
7/13. Male pseudohermaphroditism, partial androgen receptors defect, 11p13 deletion: indication of gene localization.A partial androgen receptor defect was found in a boy with male pseudohermaphroditism and an 11p13 deletion. We hypothesize that a gene responsible for the function or structure of androgen receptors might be localized in the 11p13 band or in close proximity to it.- - - - - - - - - - ranking = 6keywords = androgen (Clic here for more details about this article) |
8/13. 18q deletion syndrome in a child with steroid-17,20-lyase deficiency.The del (18q) syndrome is characterised by poor growth, variable mental retardation, facial dysmorphism, and abnormalities of the genitalia. In genetic males, genital abnormalities vary from testicular ectopia, and microphallus to severe hypospadias. Genetic females frequently have hypoplasia of the labia minora. We describe a child with del (18q) syndrome and severe ambiguous genitalia. serum testosterone after 4 doses of hCG (5000 IU/m2/dose) was only 50 ng/dL (expected greater than 300 ng/dL). When testicular tissue was incubated with [1,2-3H]progesterone and 17-hydroxy-[4-14C]progesterone, there was synthesis of 17-hydroxy-[1,2-3H]progesterone but no further metabolism of 17-hydroxyprogesterone to androgens. These data suggested the presence of steroid-17,20-lyase deficiency. In order to determine if steroid-17,20-lyase deficiency was a common feature in del (18q) syndrome we examined 6 other patients (3 girls; 3 boys) with a deletion of the long arm of chromosome 18 distal to band q21. All 6 had dehydroepiandrosterone sulfate (DHEA-S) levels which were lower than those of age-matched controls. Four had delayed puberty. serum testosterone levels were also low in 2 of the 3 affected boys. These results together with the findings in the index case suggest that a structural or regulatory gene for steroid-17,20-lyase may be located on the long arm of chromosome 18, distal to band q21.- - - - - - - - - - ranking = 1keywords = androgen (Clic here for more details about this article) |
9/13. Mild phenotypic effects of a de novo deletion Xpter-->Xp22.3 and duplication 3pter-->3p23.We report on a girl with a de novo monosomy Xpter-->Xp22.3 and trisomy 3pter-->3p23, normal development and stature, mildly affected phenotype, and learning disabilities with a low normal level of intelligence. Late replication studies using BudR demonstrated that the entire der(X) was inactive in 30% of cells. In 62% of cells the inactivation did not spread to the autosomal segment in the der(X). The normal X was inactivated in 8% of cells. Quantitative X-inactivation studies using the human androgen receptor locus assay (HAR) on peripheral leukocytes and buccal epithelial cells showed extreme skewing of methylation (90.4% of the paternal allele). The correlation of cytogenetic and molecular data suggest that the mild phenotype of the proposita is most likely due to preferential inactivation of the entire der(X), which seems to be of paternal origin.- - - - - - - - - - ranking = 1keywords = androgen (Clic here for more details about this article) |
10/13. Desmoid fibromatosis is a clonal process.Desmoid fibromatosis is a locally aggressive proliferative soft tissue lesion of controversial nature. The authors investigated the clonality of this process by molecular genetic analysis of dna methylation pattern at a polymorphic site at the human androgen-receptor gene (HUMARA) to examine the inactivation pattern of the x chromosome. Twenty desmoid fibromatoses including primary and recurrent lesions from 11 female patients were studied. Sixteen lesions from eight patients showed nonrandom X inactivation, consistent with a clonal origin and, therefore, a true neoplastic nature. Furthermore, multiple recurrent lesions from two patients exhibited the same inactivation pattern as the corresponding primary lesions, suggesting that they were derived from the same cell clone as the primary lesion. One patient was homozygous at the HUMARA locus, and two patients had the same skewed pattern in their normal and lesional tissues. The authors also found that digestion with HpaII, but not HhaI, failed to generate a nonrandom X inactivation pattern in some of the cases, suggesting that the methylation status at the HpaII sites was altered in some lesions, and that HhaI should be used to verify results and to avoid incorrect conclusions.- - - - - - - - - - ranking = 1keywords = androgen (Clic here for more details about this article) |
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