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Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

Martine Cools UGent, Piet Hoebeke UGent, KP Wolffenbuttel, H Stoop, R Hersmus, M Barbaro, A Wedell, H Brüggenwirth, LHJ Looijenga and SLS Drop (2012) EUROPEAN JOURNAL OF ENDOCRINOLOGY. 166(2). p.341-349
abstract
Objective: Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty and on germ cell tumor risk in patients with SF-1 mutations. This study reports on the natural course during puberty and on gonadal histology in two adolescents with SF-1 mutations and predominantly female phenotype at birth. Design and methods: Clinical and hormonal data and histopathological studies are reported in one male and one female adolescent with, respectively, a nonsense mutation (c. 9TOA, p. Tyr3X) and a deletion of the first two coding exons (NCBI36/hg18 Chr9: g.(126306276-126307705)_(126303229126302828) del) of NR5A1, both predicted to fully disrupt gene function. Results: LH and testosterone concentrations were in the normal male range, virilization was disproportionate to the neonatal phenotype. In the girl, gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ. In the boy, at the age of 12, numerous germ cells without signs of malignancy were present in bilateral testicular biopsy specimen. Conclusions: In SF-1 mutations, the neonatal phenotype poorly predicts virilization at puberty. Even in poorly virilized cases at birth, male gender assignment may allow spontaneous puberty without signs of hypogonadotropic hypogonadism, and possibly fertility. Patients with SF-1 mutations are at increased risk for malignant germ cell tumors. In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted. The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
GENE, LIVER RECEPTOR HOMOLOG-1, DISORDERS, XY PATIENT, 46, SEX DEVELOPMENT, FACTOR-1 SF-1, FETAL LEYDIG-CELL, ADRENAL INSUFFICIENCY, SF1, STEROIDOGENIC FACTOR-I
journal title
EUROPEAN JOURNAL OF ENDOCRINOLOGY
Eur. J. Endocrinol.
volume
166
issue
2
pages
341 - 349
Web of Science type
Article
Web of Science id
000300295000025
JCR category
ENDOCRINOLOGY & METABOLISM
JCR impact factor
3.136 (2012)
JCR rank
51/121 (2012)
JCR quartile
2 (2012)
ISSN
0804-4643
DOI
10.1530/EJE-11-0392
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2070561
handle
http://hdl.handle.net/1854/LU-2070561
date created
2012-03-21 08:54:17
date last changed
2012-04-13 10:56:00
@article{2070561,
  abstract     = {Objective: Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty and on germ cell tumor risk in patients with SF-1 mutations. This study reports on the natural course during puberty and on gonadal histology in two adolescents with SF-1 mutations and predominantly female phenotype at birth. 
Design and methods: Clinical and hormonal data and histopathological studies are reported in one male and one female adolescent with, respectively, a nonsense mutation (c. 9TOA, p. Tyr3X) and a deletion of the first two coding exons (NCBI36/hg18 Chr9: g.(126306276-126307705)\_(126303229126302828) del) of NR5A1, both predicted to fully disrupt gene function. 
Results: LH and testosterone concentrations were in the normal male range, virilization was disproportionate to the neonatal phenotype. In the girl, gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ. In the boy, at the age of 12, numerous germ cells without signs of malignancy were present in bilateral testicular biopsy specimen. 
Conclusions: In SF-1 mutations, the neonatal phenotype poorly predicts virilization at puberty. Even in poorly virilized cases at birth, male gender assignment may allow spontaneous puberty without signs of hypogonadotropic hypogonadism, and possibly fertility. Patients with SF-1 mutations are at increased risk for malignant germ cell tumors. In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted. The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation.},
  author       = {Cools, Martine and Hoebeke, Piet and Wolffenbuttel, KP and Stoop, H and Hersmus, R and Barbaro, M and Wedell, A and Br{\"u}ggenwirth, H and Looijenga, LHJ and Drop, SLS},
  issn         = {0804-4643},
  journal      = {EUROPEAN JOURNAL OF ENDOCRINOLOGY},
  keyword      = {GENE,LIVER RECEPTOR HOMOLOG-1,DISORDERS,XY PATIENT,46,SEX DEVELOPMENT,FACTOR-1 SF-1,FETAL LEYDIG-CELL,ADRENAL INSUFFICIENCY,SF1,STEROIDOGENIC FACTOR-I},
  language     = {eng},
  number       = {2},
  pages        = {341--349},
  title        = {Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth},
  url          = {http://dx.doi.org/10.1530/EJE-11-0392},
  volume       = {166},
  year         = {2012},
}

Chicago
Cools, Martine, Piet Hoebeke, KP Wolffenbuttel, H Stoop, R Hersmus, M Barbaro, A Wedell, H Brüggenwirth, LHJ Looijenga, and SLS Drop. 2012. “Pubertal Androgenization and Gonadal Histology in Two 46,XY Adolescents with NR5A1 Mutations and Predominantly Female Phenotype at Birth.” European Journal of Endocrinology 166 (2): 341–349.
APA
Cools, Martine, Hoebeke, P., Wolffenbuttel, K., Stoop, H., Hersmus, R., Barbaro, M., Wedell, A., et al. (2012). Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth. EUROPEAN JOURNAL OF ENDOCRINOLOGY, 166(2), 341–349.
Vancouver
1.
Cools M, Hoebeke P, Wolffenbuttel K, Stoop H, Hersmus R, Barbaro M, et al. Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth. EUROPEAN JOURNAL OF ENDOCRINOLOGY. 2012;166(2):341–9.
MLA
Cools, Martine, Piet Hoebeke, KP Wolffenbuttel, et al. “Pubertal Androgenization and Gonadal Histology in Two 46,XY Adolescents with NR5A1 Mutations and Predominantly Female Phenotype at Birth.” EUROPEAN JOURNAL OF ENDOCRINOLOGY 166.2 (2012): 341–349. Print.