A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.

Julie Sarfati , Anne Guiochon-Mantel (1, 2) , Philippe Rondard (3) , Isabelle Arnulf (4) , Alfons Garcia-Piñero , Slawomir Wolczynski , Sylvie Brailly-Tabard (1, 2) , Maud Bidet , Maria Ramos-Arroyo , Michèle Mathieu (5) , Anne Lienhardt-Roussie , Graeme Morgan , Zinet Turki , Catherine Bremont , James Lespinasse (6) , Hélène Du Boullay , Nathalie Chabbert-Buffet , Sébastien Jacquemont (7) , Gérard Reach , Nicole de Talence , Paolo Tonella , Bernard Conrad , Francois Despert , Bruno Delobel (8) , Thierry Brue (9) , Claire Bouvattier , Sylvie Cabrol , Michel Pugeat , Arnaud Murat , Philippe Bouchard (10) , Jean-Pierre Hardelin , Catherine Dodé , Jacques Young (1, 11)

1 Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique
2 Service de génétique moléculaire, pharmacogénétique et hormonologie
3 IGF - Institut de Génomique Fonctionnelle
4 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
5 Head of the Department of Medical Genetics
6 Département de Génétique Chromosomique
7 Service de génétique médicale
8 Centre de Génétique Chromosomique
9 CRN2M - Centre de recherche en neurobiologie - neurophysiologie de Marseille
10 LMGE - Laboratoire Microorganismes : Génome et Environnement
11 Service d'Endocrinologie et Maladies de la reproduction

Context: 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. Design and Patients: 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. Conclusion: 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.

Domaines: Biochimie [q-bio.BM]

Julie Sarfati, Anne Guiochon-Mantel, Philippe Rondard, Isabelle Arnulf, Alfons Garcia-Piñero, et al.. A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.. Journal of Clinical Endocrinology and Metabolism, 2010, 95 (2), pp.659-69. ⟨10.1210/jc.2009-0843⟩. ⟨hal-00625329⟩