kallmann syndrome and idiopathic normosmic hypogonadism … · 2017-01-12 · kallmann syndrome and...
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Kallmann syndrome and Idiopathic normosmichypogonadism patients: a multicenter Belgian study
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Valdes Socin H, Libioulle C, Debray FG, Pintiaux A, Parent AS, Corman V, Gellner K, Geenen V, Burlacu C, Jonas,
Maiter D ,T’sjoen G, Poppe K, Brachet C, Dideberg V, Bours V, Beckers A.
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Dr Aureliano Maestre de San Juan El Siglo Médico 1856;3: 211-21.
Dr Franz KallmannAm J Ment Def 1944;158:203-236.
HYPOGONADISM-DELAYED PUBERTY
T1 T2 T3 T4 T5
LH & FSH testosterone - estradiol
LH & FSH estradiol -progesterone
Nasal Placode
Anterior Pituitary
Gonads
Hypothalamus
(Kallmann Syndrome)
KAL-1 / Anosmin-1
KAL-2 / FGFR1
KAL-3 / Prok2
KAL-4 / Prok2R
KAL-5 / CHD7
KAL-6 / FGF8
KAL-7 / FEZF1
FGF8
FGF17
NELF
WDR11
FLRT3
SPRY4
SEMA3A
IL17RD
TAC3 - TAC3R
LEP - LEPR
HESX1 SPRY4
IL17R
HS6ST1
DUSP6
KISS1 - GPR54
GnRHR
LH β
FSH β
GnRH1
GnRH neurons migration
Testosterone/Estradiol
Gametogenesis
(Normosmic IHH)
*Valdes-Socin & al
Congenital Hypogonadotropic Hypogonadism *
Valdes-Socin & al. New England Journal of Medicine 2004
Valdes-Socin & al. J Clin Endoc Metabol 2009
*
*
AIM of the Study
• To study patients with CHH and :
– Explore genetic causes , by studying a large panel of 16 genes of CHH
– Describe clinical phenotype, including neurological abnormalities
– Describe sexual and fertility therapeutic results
METHODS
KAL1
FGFR1
FGF8
PROK2
PROKR2
CHD7
KISS1
KISS1R
TAC3
TACR3
GNRH1
GNRHR
NELF
WDR11
HS6ST1
SEMA3A
Targeted Next Generation Sequencing
Set of 16 Genes
• 35 patients (32H/3F) , 18±9 years
• 31 families.
• By olfactometry: 26 nIHH et 9 KS.
• 2 patients : Chiari type I malformation,
• 2 patients with empty sella ,
• 1 patient with Rathke cleft cyst
• 1 patient with cleft palate.
• Oligospermia obtained in 6/12 males after hCG & FSH. Secondary sexual characters observed in all patients.
• 1 patient with FGFR1:c.937-1234C>T mutation had a spontaneous hypogonadism reversibility after 4 years of treatment.
RESULTS (I)
Chiari Malformation & FGFR1 ?-Kumar & al . Pituitary2010-Urbizu & al. Plos One 2013
RESULTS (II)
RESULTS (III)
mutation FGFR1 (KAL2) in 3 patients and one family (3 siblings):
-c.1663+1G>A, -c.1025T>A (p.Leu342*) -c.937-1234C>T (new mutation, exon 8a of isoform IIIb).
Mutation Anosmin (KAL1) in 3 patients:
-c.1903 C>7, p.Gln635-c.827_856+49delins, p.Ala276-Asp286delinsGlyAsn
Mutation TAC3c.238+1G>A in one patient.
3 new mutations!!!
Genetic Results
ongoing study
mutations10 patients
10
25 patients
LIMITATIONS & PERSPECTIVES
• Ongoing study: panel of genes and clinical observations still not completed. Oligogenicity?
• Nearly 100 patients under study!!
• To do the first epidemiological survey of CHH in Belgium
• Correlations between genetics and clinical phenotype: – To Adapt treatment, impact in fertility
– Hypogonadism reversibility
– Inside in neurodevelopmental genes : FGFR1, Chiari malformation?
Thank you for your attention !
Service de Génétique
Dr Cecile LIBIOULLE
Dr Vinciane DIDEBERG
Prof FG DEBRAY
Prof V BOURS
Service d’Urologie
Dr Luc COPPENS
Dr Robert ANDRIANNE
Prof David WALTREGNY
Service de Gynécologie
Prof Axelle PINTIAUX
Service de Pédiatrie
Prof Anne-Simone PARENT
Service d’Endocrinologie
Dr Vinciane CORMAN
Prof Vincent GEENEN
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