1/51. Polyneuropathy with minifascicle formation in a patient with 46XY mixed gonadal dysgenesis. A patient with mixed gonadal dysgenesis showed glove and stocking-type sensory impairment and slowing of motor and sensory nerve conduction. sural nerve biopsy revealed minifascicular formation with decreased density of myelinated fibers. As far as we are aware, this is the first report of polyneuropathy with minifascicular formation in 46XY mixed gonadal dysgenesis. ( info) |
| We describe a patient who was assigned female at birth because of genital ambiguity without performing further diagnostic procedures and presented at the age of 13-1/2 years because of her strong desire to change her legal sex. karyotype was 46,XY; clinical, endocrinological, radiological and surgical work-up revealed hypergonadotropic hypogonadism and mixed gonadal dysgenesis. gender identity reversal was performed after extensive psychological testing and adaptation of living circumstances resulting in a successful integration as a male with normal psychological and social functioning. In several surgical procedures, the streak gonad, the nonfunctional testis, and the rudimentary uterus were removed, and a penis was reconstructed from a penisoid with chorda and hypospadias. Our patient supports the idea that gender identity is imprinted prenatally by hitherto poorly understood mechanisms and that sex assignment in infants with ambiguous genitalia needs careful consideration of not solely endocrinological and anatomical data. ( info) |
3/51. A novel missense mutation in the HMG box region of the SRY gene in a Japanese patient with an XY sex reversal. The sex-determining region of the y chromosome, the SRY gene, located on the short arm of the y chromosome, is appreciated as one of the genes that is responsible for directing the process of sex differentiation. To date, 34 different mutations, including 29 missense and nonsense mutations in the SRY gene, have been described in XY female patients. We investigated the molecular basis of the sex reversal in one Japanese XY female patient by determining the nucleotide sequence of the SRY gene, using polymerase chain reaction and direct sequencing. We identified a novel mutation, of the substitution of Tyr for Asn at nucleotide position 87 (N87Y). This Asn residue is located within the dna-binding high-mobility-group (HMG) motif, which is considered to be the main functional domain of the SRY protein. Further, this amino acid, Asn, is a conserved residue among mammalian SRY genes. These findings indicate that this amino acid substitution may be responsible for the sex reversal in this patient. ( info) |
| A 45,X/46,Xidic(Y)(q11.2) mosaicism was found in a 4-year-old boy. The clinical appearance was characterized by bilateral cryptorchidism, penoscrotal hypospadias, short penis, and coarctation of the aorta. The latter is the only abnormality also seen in turner syndrome. A biopsy of the gonads revealed normal prepubertal testicular tissue. A chromosome analysis in all boys with penoscrotal, scrotal, or perineal hypospadias and a thorough examination of the heart in children with 45,X/46,XY mosaicism are recommended. ( info) |
| Intersexual genitals or distinct hypospadias in combination with maldescended testis can be caused by endocrinological as well as chromosomal abnormalities. Even in early childhood such clinical findings require specific diagnostic procedures and subsequent treatment which is often invasive but has special importance as regards the early diagnosis of gonadal tumors. We present a child with cryptorchidism on the right, inguinal testis on the left and penoscrotal hypospadias. Cytogenetic analyses revealed a mosaic karyotype 45, X/46, X, idic (Yp) with unequal distribution of the mosaic in different tissues. In consequence of this chromosomal aberration the patient had mixed gonadal dysgenesis which is associated with an increased risk of tumor development in the aberrant gonads. The principles of pediatric, urological, cytogenetic and endocrinological diagnostics and the mode of data collection in the presented case are described and discussed. Furthermore, a protocol for preventive screening is presented, which combines urological and endocrinological investigations in males with malformations of the genito-urinary tract to minimize the risk of tumor development in the aberrant gonads. ( info) |
6/51. Twenty-four hour, non-invasive, neonatal chromosome analysis--application in a case of mixed gonadal dysgenesis. INTRODUCTION: With the advent of interphase molecular fluorescent in-situ hybridisation (FISH), buccal mucosa can be used to provide an highly accurate assessment of those chromosomes most commonly causing abnormality in live-born children. CLINICAL PICTURE: A newborn child presented with ambiguous genitalia. The phallus-looking enlarged "clitoris" had a urethral opening at the ventral surface near the tip and the "labial" folds were completely fused. No definite gonads were palpable. Differential diagnostic possibilities included sex chromosome or a single gene abnormality such as congenital adrenal hyperplasia. Thus, one initial objective was to investigate the sex chromosomes. Buccal mucosa was used in conjunction with fluorescent molecular probes for the X and Y. This methodology enabled a firm diagnosis of a 45,X/46,XY mosiac to be made within 24 hours. Decisions could then be made concerning gender assignment. TREATMENT AND OUTCOME: Intervention by means of reconstructive surgery of the external genitalia would be made available at a later date. CONCLUSIONS: The use of buccal mucosa is non-invasive, easy to obtain and, when combined with molecular techniques, is reliable and accurate. The clinical implication of this methodology is that it will be especially useful in gender assignment or when rapid decisions on live-saving surgery have to be made in cases of possible aneuploidy. ( info) |
7/51. Monozygotic twins of opposite sex. Although discordant karyotypes are known in identical twins, cases involving differences in sex phenotype are rare. We studied identical twins with the 46,XY karyotype - a male with mixed gonadal dysgenesis and a female with "pure" gonadal dysgenesis. The testis-determining SRY gene was present in dna from both twins but no mutations were detected in the SRY conserved motif. Monozygosity was indicated by short tandem repeat polymorphism analysis. These observations could be attributed to (i) mutation and mosaicism involving "downstream" sex-determining loci, (ii) variable penetrance of genes such as DSS/NR0B1, duplication of which can disrupt the male-determining pathway, or (iii) occurrence of cryptic 45,X gonadal cell lines. ( info) |
8/51. Laparoscopic gonadectomy and excision of mullerian remnant in an adult intersex patient. laparoscopy can assist in the diagnosis and treatment of intersex patients. We report a rare case in which laparoscopic gonadectomy and hysterosalpingectomy were performed in a phenotypically-male intersex patient first diagnosed in adulthood. ( info) |
9/51. Cytogenetic and molecular characterization of two isodicentric Y chromosomes. We report the results of detailed molecular-cytogenetic studies of two isodicentric Y [idic(Y)] chromosomes identified in patients with complex mosaic karyotypes. We used fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) to determine the structure and genetic content of the abnormal chromosomes. In the first patient, classical cytogenetics and FISH analysis with y chromosome-specific probes showed in peripheral blood lymphocytes a karyotype with 4 cell lines: 45,X[128]/46,X, idic(Y)(p11.32)[65]/47,XY, idic(Y)(p11.32)[2]/47,X, 2idic(Y)(p11. 32)[1]. No y chromosome material was found in the removed gonads. For precise characterization of the Yp breakpoint, FISH and fiberFISH analysis, using a telomeric probe and a panel of cosmid probes from the pseudoautosomal region PAR1, was performed. The results showed that the breakpoint maps approximately 1,000 Kb from Ypter. The second idic(Y) chromosome was found in a boy with mild mental retardation, craniofacial anomalies, and the karyotype in lymphocytes 47,X, idic(Y)(q11.23), i(Y)(p10)[77]/46,X, i(Y)(p10)[23]. To our knowledge, such an association has not been previously described. FISH and PCR analysis indicated the presence of at least two copies of the SRY gene in all analyzed cells. Using 17 PCR primers, the Yq breakpoint was shown to map between sY123 (DYS214) and sY121 (DYS212) loci in interval 5O in AZFb region. Possible mechanisms of formation of abnormal Y chromosomes and karyotype-phenotype correlations are discussed. ( info) |
| A girl aged 5 years and 6 months presented with premature thelarche in our outpatient clinic. During long-term observation, we recorded growth acceleration, advanced bone age, and elevated oestradiol levels which together were taken to confirm the diagnosis of precocious puberty. The patient was successfully treated with a gonadotropin-releasing hormone agonist, but in view of the poor growth prognosis, recombinant human growth hormone was administered concurrently. At the age of 9 years and 6 months a mild clitoris enlargement and conspicuous muscle development without any further signs of virilization were noticed. Laboratory findings showed high values for testosterone and normal basal values for 17-hydroxyprogesterone and dehydroepinadrosterone sulphate. Explorative laparotomy revealed a gonadoblastoma arising from testicular structures on the left, a female streak gonad on the right side, and normal uterus and fallopian tubes. The karyotype was 46,XY/45,X. These findings confirmed the diagnosis of mixed gonadal dysgenesis with testosterone-producing gonadoblastoma. ( info) |