A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.
BACKGROUND
Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS).


OBJECTIVE
The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes.


METHODS
We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2.


RESULTS
Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 +/- 0.4 vs. 4.5 +/- 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 +/- 0.1 vs. 0.7 +/- 0.8 ng/ml; P = 0.05, 0.3 +/- 0.1 vs. 1.8 +/- 3.0 IU/liter; P < 0.05, and 0.8 +/- 0.8 vs. 5.2 +/- 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 +/- 4.2 kg/m(2) in males and 26.3 +/- 6.6 kg/m(2) in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases.


CONCLUSIONS
Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations.
Sarfati
Julie
J
Service d'Endocrinologie, Hôpital Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.
Guiochon-Mantel
Anne
A
Rondard
Philippe
P
Arnulf
Isabelle
I
Garcia-Piñero
Alfons
A
Wolczynski
Slawomir
S
Brailly-Tabard
Sylvie
S
Bidet
Maud
M
Ramos-Arroyo
Maria
M
Mathieu
Michèle
M
Lienhardt-Roussie
Anne
A
Morgan
Graeme
G
Turki
Zinet
Z
Bremont
Catherine
C
Lespinasse
James
J
Du Boullay
Hélène
H
Chabbert-Buffet
Nathalie
N
Jacquemont
Sébastien
S
Reach
Gérard
G
De Talence
Nicole
N
Tonella
Paolo
P
Conrad
Bernard
B
Despert
Francois
F
Delobel
Bruno
B
Brue
Thierry
T
Bouvattier
Claire
C
Cabrol
Sylvie
S
Pugeat
Michel
M
Murat
Arnaud
A
Bouchard
Philippe
P
Hardelin
Jean-Pierre
JP
Dodé
Catherine
C
Young
Jacques
J
D000483:Alleles; D015992:Body Mass Index; D002940:Circadian Rhythm; D003456:Cryptorchidism / Q000453:epidemiology; D005260:Female; D005768:Gastrointestinal Hormones / Q000235:genetics*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics*; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*; D013737:Testis / Q000473:pathology; D013739:Testosterone / Q000378:metabolism
D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D013739:Testosterone; D006854:Hydrocortisone