Abstract
Introduction: Differences of sex development (DSD) is a group of rare congenital conditions defined by chromosomal, gonadal and/or phenotypic discordance or atypical sex. The mini-puberty, corresponding to the transient postnatal activation of the hypothalamic-pituitary-gonadal axis, is an important diagnosis window in the clinical workup of infants with DSD. First objective was to compare clinical data as well as hormone levels during minipuberty between patients with and without a genetic diagnosis. Secondary objective was to assess the positive predictive value of specific hormone levels at M2, which represents the mid-point of mini-puberty, to differentiate between patients with and without a genetic diagnosis by NGS. Methods: Our study included 57 children with 46,XY DSD born between September 2010 and August 2022 who had results from hormone level measurements during mini-puberty and a next-generation sequencing DSD gene panel. Results: From genetic testing, the diagnostic yield was 49%. Hormone analysis during mini-puberty demonstrated variations in anti-Müllerian hormone, inhibin B, follicle-stimulating hormone and luteinizing hormone levels, with specific patterns observed in certain DSD conditions. Notably, levels of follicle-stimulating hormone >4 IU/L, anti-Müllerian hormone <235 pmol/L, and inhibin B <189 pg/mL at 2 months of life were associated with a higher probability of a genetic diagnosis. Conclusion: This study proposes a less invasive diagnostic approach for 46,XY DSD children with palpable gonads at birth; it seems a single blood test around the second month of life for comprehensive analysis.
Journal Section:
Research Article
References
1.
Lanciotti
L
, Cofini
M
, Leonardi
A
, Penta
L
, Esposito
S
. Up-to-date review about minipuberty and overview on hypothalamic-pituitary-gonadal axis activation in fetal and neonatal life
. Front Endocrinol
. 2018
;9
:410
. 2.
Kuiri-Hänninen
T
, Sankilampi
U
, Dunkel
L
. Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty
. Horm Res Paediatr
. 2014
;82
(2
):73
–80
. 3.
4.
Renault
CH
, Aksglaede
L
, Wøjdemann
D
, Hansen
AB
, Jensen
RB
, Juul
A
. Minipuberty of human infancy: a window of opportunity to evaluate hypogonadism and differences of sex development
. Ann Pediatr Endocrinol Metab
. 2020
;25
(2
):84
–91
. 5.
Busch
AS
, Ljubicic
ML
, Upners
EN
, Fischer
MB
, Raket
LL
, Frederiksen
H
, et al. Dynamic changes of reproductive hormones in male minipuberty: temporal dissociation of leydig and Sertoli cell activity
. J Clin Endocrinol Metab
. 2022
;107
(6
):1560
–8
. 6.
Ljubicic
ML
, Busch
AS
, Upners
EN
, Fischer
MB
, Main
KM
, Andersson
A-M
, et al. Dynamic changes in LH/FSH ratios in infants with normal sex development
. Eur J Endocrinol
. 2022
;187
(1
):135
–42
. 7.
Blackless
M
, Charuvastra
A
, Derryck
A
, Fausto-Sterling
A
, Lauzanne
K
, Lee
E
. How sexually dimorphic are we? Review and synthesis
. Am J Hum Biol
. 2000
;12
(2
):151
–66
. 8.
Arboleda
VA
, Lee
H
, Sánchez
FJ
, Délot
EC
, Sandberg
DE
, Grody
WW
, et al. Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development
. Clin Genet
. 2013
;83
(1
):35
–43
. 9.
Eggers
S
, Sadedin
S
, van den Bergen
JA
, Robevska
G
, Ohnesorg
T
, Hewitt
J
, et al. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
. Genome Biol
. 2016
;17
(1
):243
. 10.
Dong
Y
, Yi
Y
, Yao
H
, Yang
Z
, Hu
H
, Liu
J
, et al. Targeted next-generation sequencing identification of mutations in patients with disorders of sex development
. BMC Med Genet
. 2016
;17
:23
. 11.
Hughes
LA
, McKay-Bounford
K
, Webb
EA
, Dasani
P
, Clokie
S
, Chandran
H
, et al. Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD)
. Endocr Connect
. 2019
;8
(2
):100
–10
. 12.
Gomes
NL
, Batista
RL
, Nishi
MY
, Lerário
AM
, Silva
TE
, de Moraes Narcizo
A
, et al. Contribution of clinical and genetic approaches for diagnosing 209 index cases with 46,XY differences of sex development
. J Clin Endocrinol Metab
. 2022
;107
(5
):e1797
–806
. 13.
Xie
Q-G
, Luo
P
, Xia
K
, Li
Z-Q
, Xu
Z
, Su
C
, et al. 46,XY disorders of sex development: the use of NGS for prevalent variants
. Hum Genet
. 2022
;141
(12
):1863
–73
. 14.
Yu
B-Q
, Liu
Z-X
, Gao
Y-J
, Wang
X
, Mao
J-F
, Nie
M
, et al. Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing
. Asian J Androl
. 2021
;23
(1
):69
–73
. 15.
Kim
JH
, Kang
E
, Heo
SH
, Kim
G-H
, Jang
J-H
, Cho
E-H
, et al. Diagnostic yield of targeted gene panel sequencing to identify the genetic etiology of disorders of sex development
. Mol Cell Endocrinol
. 2017
;444
:19
–25
. 16.
Miclea
D
, Alkhzouz
C
, Bucerzan
S
, Grigorescu-Sido
P
, Popp
RA
, Pascanu
IM
, et al. Molecular and cytogenetic analysis of Romanian patients with differences in sex development
. Diagn Basel Switz
. 2021
;11
:2107
. 17.
Özen
S
, Onay
H
, Atik
T
, Solmaz
AE
, Özkınay
F
, Gökşen
D
, et al. Rapid molecular genetic diagnosis with next-generation sequencing in 46,XY disorders of sex development cases: efficiency and cost assessment
. Horm Res Paediatr
. 2017
;87
(2
):81
–7
. 18.
Hughes
IA
, Houk
C
, Ahmed
SF
, Lee
PA
; LWPES Consensus Group
, ESPE Consensus Group
. Consensus statement on management of intersex disorders
. Arch Dis Child
. 2006
;91
(7
):554
–63
. 19.
Wisniewski
AB
, Batista
RL
, Costa
EMF
, Finlayson
C
, Sircili
MHP
, Dénes
FT
, et al. Management of 46,XY differences/disorders of sex development (DSD) throughout life
. Endocr Rev
. 2019
;40
(6
):1547
–72
. 20.
Guerrero-Fernández
J
, Azcona San Julián
C
, Barreiro Conde
J
, Bermúdez de la Vega
JA
, Carcavilla Urquí
A
, Castaño González
LA
, et al. Management guidelines for disorders/different sex development (DSD)
. Pediatr
. 2018
;89
(5
):315.e1
–9
. 21.
Cools
M
, Nordenström
A
, Robeva
R
, Hall
J
, Westerveld
P
, Flück
C
, et al. Caring for individuals with a difference of sex development (DSD): a Consensus Statement
. Nat Rev Endocrinol
. 2018
;14
(7
):415
–29
. 22.
van der Straaten
S
, Springer
A
, Zecic
A
, Hebenstreit
D
, Tonnhofer
U
, Gawlik
A
, et al. The External Genitalia Score (EGS): a European multicenter validation study
. J Clin Endocrinol Metab
. 2020
;105
(3
):dgz142
. 23.
Salenave
S
, Chanson
P
, Bry
H
, Pugeat
M
, Cabrol
S
, Carel
JC
, et al. Kallmann’s syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations
. J Clin Endocrinol Metab
. 2008
;93
(3
):758
–63
. 24.
Maione
L
, Fèvre
A
, Nettore
IC
, Manilall
A
, Francou
B
, Trabado
S
, et al. Similarities and differences in the reproductive phenotypes of women with congenital hypogonadotrophic hypogonadism caused by GNRHR mutations and women with polycystic ovary syndrome
. Hum Reprod
. 2019
;34
(1
):137
–47
. 25.
Trabado
S
, Maione
L
, Salenave
S
, Baron
S
, Galland
F
, Bry-Gauillard
H
, et al. Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment
. Fertil Steril
. 2011
;95
(7
):2324–9, 2329.e1–3
. 26.
Mosbah
H
, Bouvattier
C
, Maione
L
, Trabado
S
, De Filippo
G
, Cartes
A
, et al. GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty
. Hum Reprod
. 2020
;35
(10
):2312
–22
. 27.
Bry-Gauillard
H
, Larrat-Ledoux
F
, Levaillant
J-M
, Massin
N
, Maione
L
, Beau
I
, et al. Anti-müllerian hormone and ovarian morphology in women with isolated hypogonadotropic hypogonadism/kallmann syndrome: effects of recombinant human FSH
. J Clin Endocrinol Metab
. 2017
;102
(4
):1102
–11
. 28.
Garagorri
JM
, Rodríguez
G
, Lario-Elboj
AJ
, Olivares
JL
, Lario-Muñoz
A
, Orden
I
. Reference levels for 17-hydroxyprogesterone, 11-desoxycortisol, cortisol, testosterone, dehydroepiandrosterone sulfate and androstenedione in infants from birth to six months of age
. Eur J Pediatr
. 2008
;167
(6
):647
–53
. 29.
Johannsen
TH
, Main
KM
, Ljubicic
ML
, Jensen
TK
, Andersen
HR
, Andersen
MS
, et al. Sex differences in reproductive hormones during mini-puberty in infants with normal and disordered sex development
. J Clin Endocrinol Metab
. 2018
;103
(8
):3028
–37
. 30.
Bergadá
I
, Milani
C
, Bedecarrás
P
, Andreone
L
, Ropelato
MG
, Gottlieb
S
, et al. Time course of the serum gonadotropin surge, inhibins, and anti-Müllerian hormone in normal newborn males during the first month of life
. J Clin Endocrinol Metab
. 2006
;91
(10
):4092
–8
. 31.
Baux
D
, Van Goethem
C
, Ardouin
O
, Guignard
T
, Bergougnoux
A
, Koenig
M
, et al. MobiDetails: online DNA variants interpretation
. Eur J Hum Genet
. 2021
;29
(2
):356
–60
. 32.
Kopanos
C
, Tsiolkas
V
, Kouris
A
, Chapple
CE
, Albarca Aguilera
M
, Meyer
R
, et al. VarSome: the human genomic variant search engine
. Bioinforma Oxf Engl
. 2019
;35
(11
):1978
–80
. 33.
Rey
RA
. Next-generation sequencing as first-line diagnostic test in patients with disorders of sex development
. J Clin Endocrinol Metab
. 2022
;107
(6
):e2628
–29
. 34.
Bouvattier
C
, Carel
J-C
, Lecointre
C
, David
A
, Sultan
C
, Bertrand
A-M
, et al. Postnatal changes of T, LH, and FSH in 46,XY infants with mutations in the AR gene
. J Clin Endocrinol Metab
. 2002
;87
(1
):29
–32
. 35.
Köhler
B
, Biebermann
H
, Friedsam
V
, Gellermann
J
, Maier
RF
, Pohl
M
, et al. Analysis of the Wilms’ tumor suppressor gene (WT1) in patients 46,XY disorders of sex development
. J Clin Endocrinol Metab
. 2011
;96
(7
):E1131
–6
. © 2025 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2025
You do not currently have access to this content.
