title: Clinical and molecular studies in four patients with SRY-positive 46,XX testicular disorders of sex development: implications for variable sex development and genomic rearrangements.
abstract: We report four patients with SRY-positive 46,XX testicular disorders of sex development (46,XX-TDSD) (cases 1-4). Case 1 exhibited underdeveloped external genitalia with hypospadias, case 2 manifested micropenis and cases 3 and 4 showed normal external genitalia. The Xp;Yp translocations occurred between the X- and the Y-differential regions in case 1, between PRKX and inverted PRKY in case 2 and between the X-chromosomal short arm pseudoautosomal region and the Y-differential regions in cases 3 and 4. The distance of the Yp breakpoint from SRY was ~0.75 Mb in case 1, ~6.5 Mb in case 2, ~2.3 Mb in case 3 and ~72 kb in case 4. The Xp;Yp translocation occurred within an 87-bp homologous segment of PRKX and PRKY in case 2, and between non-homologous regions with addition of an 18-bp sequence of unknown origin in case 4. X-inactivation analysis revealed random inactivation in cases 1-4. The results argue against the notion that undermasculinization in 46,XX-TDSD is prone to occur when translocated Yp materials are small (<100 kb of the Y-differential region), and imply that the Xp;Yp translocations result from several mechanisms including non-allelic homologous recombination and non-homologous end joining.
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakashima
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohishi
authors.affiliation: Department of Medical Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Takada
authors.affiliation: Department of Urology, Shizuoka Children's Hospital, Shizuoka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kawamura
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D058531:46, XX Testicular Disorders of Sex Development / Q000235:genetics*; D000328:Adult; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D041322:Chromosomes, Human, Y; D055028:Comparative Genomic Hybridization; D059766:DNA End-Joining Repair; D005260:Female; D024282:Genes, sry; D059765:Homologous Recombination; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D014178:Translocation, Genetic; D049951:X Chromosome Inactivation; D055815:Young Adult
references.citation: J Assist Reprod Genet. 2008 Nov-Dec;25(11-12):547-52
references.pmid: 18972202
references.citation: Cell. 1987 Nov 6;51(3):417-25
references.pmid: 2822256
references.citation: Am J Med Genet. 1999 Jun 4;84(4):384-5
references.pmid: 10340659
references.citation: Am J Med Genet. 1985 May;21(1):137-42
references.pmid: 4039890
references.citation: J Med Genet. 1999 Jun;36(6):452-6
references.pmid: 10874632
references.citation: J Clin Endocrinol Metab. 2007 Aug;92(8):2868-73
references.pmid: 17488792
references.citation: Genomics. 1995 Jul 1;28(1):52-8
references.pmid: 7590747
references.citation: Curr Biol. 1998 Dec 17-31;8(25):1391-4
references.pmid: 9889101
references.citation: Arch Med Res. 2001 Nov-Dec;32(6):559-66
references.pmid: 11750731
references.citation: Hum Mol Genet. 1998;7(10):1611-8
references.pmid: 9735382
references.citation: Nature. 1989 Dec 21-28;342(6252):937-9
references.pmid: 2594087
references.citation: J Med Genet. 2005 May;42(5):420-7
references.pmid: 15863672
references.citation: Cytogenet Cell Genet. 1994;66(1):22-6
references.pmid: 8275702
references.citation: J Clin Endocrinol Metab. 2000 Sep;85(9):3094-100
references.pmid: 10999792
references.citation: Am J Med Genet. 1995 Jan 30;55(3):356-8
references.pmid: 7726236
references.citation: Adv Genet. 1995;33:275-329
references.pmid: 7484456
references.citation: Nature. 2005 Mar 17;434(7031):400-4
references.pmid: 15772666
references.citation: Eur J Pediatr. 1993;152 Suppl 2:S70-5
references.pmid: 8339747
references.citation: Methods Mol Biol. 2012;838:1-27
references.pmid: 22228005