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.
.
Dr Aureliano Maestre de San Juan El Siglo Médico 1856;3: 211-21.
Dr Franz KallmannAm J Ment Def 1944;158:203-236.
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HYPOGONADISM-DELAYED PUBERTY
T1 T2 T3 T4 T5
LH & FSH testosterone - estradiol
LH & FSH estradiol -progesterone
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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
*
*
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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
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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
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• 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)
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Chiari Malformation & FGFR1 ?-Kumar & al . Pituitary2010-Urbizu & al. Plos One 2013
RESULTS (II)
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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
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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?
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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