title: A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.
abstract: 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.
authors.affiliation: Service d'Endocrinologie, Hôpital Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Sarfati
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
authors.forename: Philippe
authors.initials: P
authors.lastname: Rondard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Arnulf
authors.forename: Alfons
authors.initials: A
authors.lastname: Garcia-Piñero
authors.forename: Slawomir
authors.initials: S
authors.lastname: Wolczynski
authors.forename: Sylvie
authors.initials: S
authors.lastname: Brailly-Tabard
authors.forename: Maud
authors.initials: M
authors.lastname: Bidet
authors.forename: Maria
authors.initials: M
authors.lastname: Ramos-Arroyo
authors.forename: Michèle
authors.initials: M
authors.lastname: Mathieu
authors.forename: Anne
authors.initials: A
authors.lastname: Lienhardt-Roussie
authors.forename: Graeme
authors.initials: G
authors.lastname: Morgan
authors.forename: Zinet
authors.initials: Z
authors.lastname: Turki
authors.forename: Catherine
authors.initials: C
authors.lastname: Bremont
authors.forename: James
authors.initials: J
authors.lastname: Lespinasse
authors.forename: Hélène
authors.initials: H
authors.lastname: Du Boullay
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chabbert-Buffet
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: Gérard
authors.initials: G
authors.lastname: Reach
authors.forename: Nicole
authors.initials: N
authors.lastname: De Talence
authors.forename: Paolo
authors.initials: P
authors.lastname: Tonella
authors.forename: Bernard
authors.initials: B
authors.lastname: Conrad
authors.forename: Francois
authors.initials: F
authors.lastname: Despert
authors.forename: Bruno
authors.initials: B
authors.lastname: Delobel
authors.forename: Thierry
authors.initials: T
authors.lastname: Brue
authors.forename: Claire
authors.initials: C
authors.lastname: Bouvattier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cabrol
authors.forename: Michel
authors.initials: M
authors.lastname: Pugeat
authors.forename: Arnaud
authors.initials: A
authors.lastname: Murat
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouchard
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hardelin
authors.forename: Catherine
authors.initials: C
authors.lastname: Dodé
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
mesh_terms: 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
chemical_list: 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