As clinicians we are trained to observe clinical cues and develop differential diagnoses. Often we are inclined to consider the most likely possibilities, yet for patients with rare disorders, this can result in lengtty delays in diagnosis. Indeed, patients with rare diseased are often initially misdiagnosed and have delays in obtaining an accurate diagnosis1). Misdiagnosis and delays in reaching a correct diagnosis can have significant repercussions on quality of life and can erode confidence in the health system. Recently, there has been growing attention to early life determinants of health and disease. This article provides a brief overview of how phenotypes in male neonates male can provide important clues that provide a neonatal window of opportunity for making and early diagnosis of disorders of puberty and reproduction later in life2).
25
As clinicians we ar e tr aine d to obser ve clinical
cues and develop differential diagnoses. \bf-
ten we are inclined to consider the most like –
ly possibilities, yet for patients with rare dis –
orders, this can result in lengtty delays in
diagnosis. Indeed, patients with rare diseased
are often initially misdiagnosed and have
delays in obtaining an accurate diagnosis
1).
Misdiagnosis and delays in reaching a correct
diagnosis can have significant repercussions
on quality of life and can erode confidence in
the health system. Recently, there has been
g row ing at tention to ear ly life deter minant s of
health and disease. This article provides a
brief overview of how phenotypes in male
neonates male can provide important clues
that provide a neonatal window of opportuni –
t y for making and ear ly diag nosis of disor der s
of puberty and reproduction later in life
2).
The impor tance of the neonatal mini – puber ty
From the first week through approximately
6-months of life, the hypothalamic-pituitary-
gonadal (HPG) axis is activated and this re –
sults in serum hormone levels in similar to
adults
3). Indeed, this is sometimes evident at
«baby acne» and male infants may have erec –
tions observed during diaper changes. In male
infants the increased levels of gonadotropins,
luteinising hormone (LH) and follicle stimula –
ting hormone (FSH) stimulate testicular deve –
lopment (i.e. Sertoli cell and spermatogonia
proliferation) as well as testosterone produc –
tion
4). This so called «mini-puberty» has pro –
liferative effects that are thought to signifi –
cantly impact future fertility. Conversely,
males who lack this developmental hormonal
surge, such as patients with congenital hy po –
gondotropic hypogonadism (CHH), Kallmann
syndrome ( KS) or combined pituitar y hormo –
ne deficiency (CPHD), can have impaired pu –
berty and fertility later in life
5). Importantly,
there are clinical clues at birth that can help
identify patients who have absent mini-puber –
t y.
Red flags of absent minipuberty: maldecen –
ded testes and micropenis Androgens (i.e.
«A Window of opportunity»
Andrew Dwyer, PhD, FNP-BC
Universite de Lausanne, Institute universitaire de fromationet de recherche en soins (IUFRS)
et Centre Hospitlaier Universitiare Vaudois (CHUV)
Boston College, William F. Connell School of Nursing, Chestnut Hill, Massachusetts, USA
testosterone, dihydrotestosterone) are criti-
cal for testicular descent and penile growth
during early life development. During fetal life,
maternal chorionic gonadotropin stimulate
the testes and is critical for masculinizing the
male genitalia. Yet LH is needed for further
penile growth and testicular descent, thus for
males with disrupted HPG axis (i.e. CHH, KS,
CPHD with LH/FSH deficiency) who lack LH
secretion, this may be clinically manifested as
maldescended testes with or without micro –
penis
5),6) . Males with cryptorchidism have
reduced numbers of Sertoli cells and sperma –
togonia and have increased risk for infertility
later in life
4). Swiss researchers using histolo –
gical analyses have demonstrated the negati –
ve impact that maldescended testes can have
on spermatogenic potential
7). This can be
mitigated by surgical correction (orchiopexy
w ithin the fir st year of life ) and microp enis can
be effectively treated with androgens during
early infancy
6). Moreover, several small stu –
dies employing hormonal treatment during
the neonatal window hold promise for optimi –
zing future fertility – yet longterm follow up of
these children is needed to determine the
impact on fertility
8). While these early inter –
ventions can have b ene ficial ef fe ct s on f utur e
fertility potential, often the window of oppor –
tunity to diagnose CHH, KS, CPHD is missed.
Confirming clinical suspicion Identifying CHH,
KS and CPDH (with LH/FSH deficiency) can
b e accomplishe d in one of t wo ways : by iden –
tifying mutations in known disease loci using
genetic testing or via hormonal profiling (tes –
tosterone, LH, FSH) during the mini-puberty
– when the HPG axis is active in the first
months of life. Genetic testing can be infor –
mative yet only a small proportion of cases
are accounted for by the known CPHD loci
and 25+ genes that have been shown to un –
derlie CHH/KS
6). Mor e over, the lo ci for CHH/
KS only account for approximately half of
cases. This should not be a deterrent for ge –
netic screening. Rather, it can complement
hormone screening (between 1 week and
6-months of life)
6). Not ably an prog r am le d by Dr. Franziska Phan-Hug has been initiated at
the CHUV to systematically screen male in
–
fants born with cryptorchidism/micropenis.
Unfortunately, all too often this window of
opportunity is missed.
Impact of missed diagnostic opportunities
Even in situations when patients have a medi –
cal history of corrected maldescended testes
or treated micropenis, these clues are often
not taken into account when patients subse –
quently present for failing to spontaneously
initiate puberty. Delayed diagnosis for adole –
scents and young men with CHH/KS is not
infrequent. A recent report identified that
men were diagnosed quite late (95 % CI : 17.6 –
20.2 years) and this delay has significant im –
pact on psychosocial wellbeing including
feelings of isolation, shame, body image
concerns as well negative effects on psycho –
sexual development
10 ). Thus attention to
these red flags can enable a timely diagnosis
and appropriate timing of treatment. This is
important as initiating treatment to induce
secondary sexual characteristics in line with
peers can help ameliorate some of the psy –
chological impact experienced by these men
– who if left untreated, are essentially young
adults trapped in an unvirilized child’s body.
This is reflected in a quote of a patient with
CHH « A ll those things ar e se e ds for psycholo –
gical damage. I mean, the stuff occurring at
that stage (adolescence) builds up and builds
up and builds up over the years…».
In summary, the mini-puberty of neonatal life
is a remarkable biologic event that appears to
have sig ni ficant impact on f utur e r epr o ducti ve
health. Signs including cryptorchidism and
micr op enis ar e imp or t ant r e d flags r aising the
suspicion of congenital disorders effecting
puberty and reproduction. It is worthwhile to
note that cryptorchidism occurs in 2-5% of
males
6) and certainly not all of these cases
will have an underlying rare disorder. Howe –
ver, clinicians should be aware that appropri –
ate evaluation of such cases can identify pa –
tients early and timely diagnosis can have
major benefits for optimizing potential fertility
and may b e a life – changing helping to pr event
or decrease psychological morbidity and en –
hance quality of life for these patients.
References
1. Eurordis. The voice of 12000 patients. Boulogne –
Billancourt, France 2009
2. Grumbach MM. A window of opportunity: the diag –
nosis of gonadotropin deficiency in the male infant.
J Clin Endocrinol Metab. 2005;90(5):3122-7.
25As cl ins a cwer
25As clinaw
26
3. Kuiri- Hänninen T, Sankilampi U, Dunkel L. Activati –
on of the hypothalamic-pituitary-gonadal axis in
infancy. Horm Res Paediatr. 2014; 82(2):73 -80.
4. Grinspon RP, Loreti N, Braslavsky D, Valeri C, Sch –
teingar t H, Ballerini MG, Bedecarrás P, Ambao V,
Gottlieb S, Ropelato MG, Bergadá I, Campo SM, Rey
RA. Spreading the clinical window for diagnosing
fetal- onset hypogonadism in boys. Front Endocri –
nol (Lausanne). 2014; 5:51
5. Dw yer A A, Jayasena CN, Quinton R. Congenital
hypogonadotropic hypogonadism: implications of
absent mini-puberty. Minerva Endocrinol. 2016;
41 ( 2 ) :1 8 8 – 9 5 .
6. Boehm U, Bouloux PM, Dattani MT, de Roux N,
Dodé C, Dunkel L, Dw yer A A, Giacobini P, Hardelin
JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio
T, Tena-Sempere M, Quinton R, Young J. Exper t
consensus statetment: European consesnus state –
ment on congenital hypogonadotrophic hypogona –
dism – pathogenesis, diagnosis and treatment. Nat
Rev Endocrinol. 2015; 11(9):547- 64.
7. Zivkovic D & Hadziselimovic F. Development of
sertoli cells during mini-puberty in normal and
cr yptorchid testes. Urol Int. 2009; 82(1):89-91.
8. Bouvattier C, Maione L, Bouligand J, Dodé C,
Guiochon-Mantel A, Young J. Neonatal gonadotro –
pin therapy in male congenital hypogonadotropic
hypogonadism. Nat Rev Endocrinol. 2011; 8(3):172-
82.
9. Quinton R, Mamoojee Y, Jayasena CN, Young J,
Howard S, Dunkel L, Cheetham T, Smith N, Dw yer
A A. Society for Endocrinology UK guidance on the
evaluation of suspected disorders of sexual deve –
lopment: emphasizing the opportunity to predict
adolescent pubertal failure through neonatal diag –
nosis of absent minipuber ty. Clin Endocrinol (Oxf ).
2017; 86(2):305 -306.
10. Dw yer A A, Quinton R, Pitteloud N, Morin D. Psycho –
sexual development in men with congenital hypo –
gonadotropic hypogonadism on long-term treat –
ment: a mixed methods study. Sex Med. 2015;
3 (1 ) : 3 2 – 41 .
Correspondence
adwyer989@gmail.com
25As cl ins a cwer
25As clinaw
Weitere Informationen
Korrespondenz:
Autoren/Autorinnen
A. Dwyer