title: Uniparental Disomy in Somatic Mosaicism 45,X/46,XY/46,XX Associated with Ambiguous Genitalia.
abstract: Disorders of sex development (DSD) affect the development of chromosomal, gonadal and/or anatomical sex. We analyzed a patient with ambiguous genitalia aiming to correlate the genetic findings with the phenotype. Blood and tissue samples from a male patient with penoscrotal hypospadias were analyzed by immunohistochemistry, karyotyping and FISH. DNA was sequenced for the AR, SRY and DHH genes, and further 26 loci in different sex chromosomes were analyzed by MLPA. The gonosomal origin was evaluated by simple tandem repeat (STR) analysis and SNP array. Histopathology revealed a streak gonad, a fallopian tube and a rudimentary uterus, positive for placental alkaline phosphatase, cytokeratin-7 and c-kit, and negative for estrogen, androgen and progesterone receptors, alpha-inhibin, alpha-1-fetoprotein, β-hCG, and oct-4. Karyotyping showed a 45,X/46,XY mosaicism, yet FISH showed both 46,XX/46,XY mosaicism (gonad and urethral plate), 46,XX (uterus and tube) and 46,XY karyotypes (rudimentary testicular tissue). DNA sequencing revealed intact sequences in SOX9, WNT4, NR0B1, NR5A1, CYP21A2, SRY, AR, and DHH. STR analysis showed only one maternal allele for all X chromosome markers (uniparental isodisomy, UPD), with a weaker SRY signal and a 4:1 ratio in the X:Y signal. Our findings suggest that the observed complex DSD phenotype is the result of somatic gonosomal mosaicism and UPD despite a normal blood karyotype. The presence of UPD warrants adequate genetic counseling for the family and frequent, lifelong, preventive follow-up controls in the patient.
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, University of Ulm, Ulm, Germany.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Serra
authors.forename: Friederike
authors.initials: F
authors.lastname: Denzer
authors.forename: Olaf
authors.initials: O
authors.lastname: Hiort
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Barth
authors.forename: Doris
authors.initials: D
authors.lastname: Henne-Bruns
authors.forename: Gotthold
authors.initials: G
authors.lastname: Barbi
authors.forename: Günther
authors.initials: G
authors.lastname: Rettenberger
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Walter
authors.initials: W
authors.lastname: Just
authors.forename: Clothilde
authors.initials: C
authors.lastname: Leriche
mesh_terms: D041321:Chromosomes, Human, X / Q000235:genetics*; D041322:Chromosomes, Human, Y / Q000235:genetics*; D003558:Cystoscopy; D012734:Disorders of Sex Development / Q000235:genetics* / Q000601:surgery; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D018895:Microsatellite Repeats / Q000235:genetics; D009030:Mosaicism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011300:Preoperative Care; D024182:Uniparental Disomy / Q000235:genetics*