Laparoscopy in the Surgical Treatment of Disorders of Sexual Development.

INTRODUCTION: Disorder of sexual development (DSD) is a rare condition. The surgical treatment of these patients includes investigation of the internal genitalia, evaluation of the gonads, and if necessary gonadectomy. The prevention of germ cell tumors is the most important issue in the surgical treatment of this varied and special group of patients. This study aimed to evaluate the role of laparoscopy in the surgical treatment of patients with DSD. MATERIALS AND METHODS: Over a 4-year-period, all patients presenting with DSD who underwent laparoscopic surgery at our institution were retrospectively reviewed. Operative procedure, age at the time of surgery, and histopathological results were evaluated. In addition, karyotypes and phenotypes were investigated. RESULTS: Altogether, 12 patients undergoing 14 laparoscopic procedures were included. Median age at the time of surgery was 6 years with a range from 9 months to 17 years. Explorative laparoscopy was performed in all patients. In seven children, laparoscopic gonadectomy was necessary. Histopathologic examination revealed germ cell tumors in four children. In two patients, a gonadoblastoma was identified; in two patients, a dysgerminoma was found. Inguinal exploration was performed in four patients and led to removal of gonadal remnants in one case and gonadopexy in three cases. In two patients presenting with repeated urinary tract infections, laparoscopic removal of an utriculus was performed. CONCLUSIONS: Laparoscopic gonadal biopsy, gonadopexy, and gonadectomy can be performed successfully, even in patients with germ cell tumors. To define guidelines for the surgical treatment of patients with DSD, further prospective and multicenter studies are necessary.

Uniparental Disomy in Somatic Mosaicism 45,X/46,XY/46,XX Associated with Ambiguous Genitalia.

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, ß-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.

Genomic variants in the coding region of neuronal nitric oxide synthase (NOS1) in infantile hypertrophic pyloric stenosis.

BACKGROUND: Infantile hypertrophic pyloric stenosis (IHPS) is a common childhood pathology affecting 1 to 5:1000 newborns, with a genetic background suggested by familial occurrence. Neuronal nitric oxide synthase (NOS1) is a candidate gene owing to its role in the relaxation of smooth musculature and the association of the -84g>a variant of NOS1 with IHPS. METHODS: We investigated NOS1 through sequencing of the complete NOS1 coding region in DNA from 43 patients with IHPS compared the genotype frequencies to 47 controls using the Cochran-Armitage trend or Fisher exact tests. RESULTS: We found 19 polymorphisms in the coding region of NOS1. The variants c.3827-42_3827-43 del_insTA and c.+276 c>t were more frequent in IHPS with statistically significant exact P values (P = .010 and P = .039, respectively) yet failed to show significance after Bonferroni adjustment for multiple testing. We have also found a marginally significant occurrence of the variants c.-460A (P = .065) and c.2823+15G (P = .076). There was a significant correlation between the variants c.2706C>T ⬄ c.2823+15A>G, (r(2) = 1.00) and c.3258 C>T ⬄ c.3235+31A>G (r(2) = 1.00). CONCLUSIONS: We conclude that NOS1 variants are present in patients with IHPS yet show no significant statistical association with the IHPS phenotype, suggesting at best an adjuvant role for NOS1 in IHPS.