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