High prevalence of primary ovarian insufficiency in girls and young women with Nijmegen breakage syndrome: evidence from a longitudinal study.
BACKGROUND
Nijmegen breakage syndrome (NBS) is a severe chromosomal instability disorder characterized by microcephaly, growth retardation, immune deficiency, and predisposition for malignancy. It is caused by hypomorphic mutations in the NBN gene, which product belongs to the protein complex critical for processing DNA double-strand breaks during mitotic and meiotic recombination. Data on gonadal function in patients with NBS are limited.


OBJECTIVE
Growth and sexual development, along with hormonal assays, were evaluated in girls and young women with NBS homozygous for c.657_661del5 mutation.


METHODS
The group comprised 37 girls and young women with NBS (ages, 0.17-24.25 yr), followed between 1993 and 2008. Patients were divided into three age groups: 1) 1-3 yr; 2) 4-9 yr; and 3) 10 yr and older. Growth, puberty, concentrations of gonadotropins and 17-beta-estradiol, bone age, and pelvic ultrasound were assessed.


RESULTS
None of the patients presented a typical growth spurt; the adult height ranged between the 3rd and 25th centiles. Median bone age was delayed by 4.05 yr. Pubarche reached stadium P2 in eight patients and P3 in two patients. In all but one girl, thelarche did not exceed Th2, with low 17beta-estradiol levels. Gonadotropin levels showed a biphasic pattern, with median FSH values of 55.0, 10.9, and 81.9 IU/liter, and LH of 3.2, 0.8, and 21.0 IU/liter in consecutive age groups. Ultrasound visualized small ovaries or solid streaks and the hypoplastic uterus.


CONCLUSIONS
Primary ovarian insufficiency and the associated hypergonadotropic hypogonadism are hallmark manifestations in girls and young women with NBS. Our findings emphasize the need for long-term endocrinological and interdisciplinary supervision of these patients.
Chrzanowska
Krystyna H
KH
Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland. k.chrzanowska@czd.pl
Szarras-Czapnik
Maria
M
Gajdulewicz
Maria
M
Kalina
Maria A
MA
Gajtko-Metera
Malgorzata
M
Walewska-Wolf
Malgorzata
M
Szufladowicz-Wozniak
Jolanta
J
Rysiewski
Henryk
H
Gregorek
Hanna
H
Cukrowska
Bozena
B
Syczewska
Malgorzata
M
Piekutowska-Abramczuk
Dorota
D
Janas
Roman
R
Krajewska-Walasek
Malgorzata
M
D000293:Adolescent; D000704:Analysis of Variance; D001827:Body Height; D002648:Child; D002675:Child, Preschool; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000150:complications / Q000453:epidemiology*; D007223:Infant; D008137:Longitudinal Studies; D007986:Luteinizing Hormone / Q000097:blood; D049932:Nijmegen Breakage Syndrome / Q000097:blood / Q000150:complications*; D015995:Prevalence; D016649:Primary Ovarian Insufficiency / Q000097:blood / Q000150:complications / Q000453:epidemiology*; D011628:Puberty, Delayed / Q000097:blood / Q000150:complications / Q000453:epidemiology*; D018709:Statistics, Nonparametric; D055815:Young Adult
D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone