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

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.

Exercise release of cardiac natriuretic peptides is markedly enhanced when patients with coronary artery disease are treated medically by beta-blockers.

OBJECTIVES: This study sought to identify determinants of the exercise rise in plasma levels of cardiac natriuretic peptides (NPs) in patients with coronary artery disease (CAD). BACKGROUND: During stress, there is a variable rise in the plasma level of NPs, but this rise frequently reaches levels that are known to lower the cardiac load and that thus might be beneficial to CAD patients. METHODS: Plasma venous concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were determined at rest and peak exercise in 104 patients with chronic CAD who were referred to exercise thallium-201 ((201)Tl) single-photon emission computed tomography (SPECT) and radionuclide angiography. RESULTS: The extent of scarred myocardium by (201)Tl-SPECT and patient age were the best independent predictors of NP concentrations at rest, but also of increases in NP concentration during exercise (all p < 0.001). Moreover, beta-blocking treatment was an additional and strong independent predictor of the increase in NP concentrations at exercise (p < 0.001 for ANP; p = 0.001 for BNP). On average, exercise increases in NP concentrations were more than twice as high in patients with (n = 55) than in those without (n = 49) beta-blocker treatment (ANP: +49 +/- 63 vs. +22 +/- 25 ng/l, p = 0.01; BNP: +24 +/- 5 vs. +11 +/- 15 ng/l, p = 0.04), whereas NP concentrations at rest were equivalent in the two groups (ANP: 34 +/- 34 vs. 30 +/- 33 ng/l, p = NS; BNP: 85 +/- 152 vs. 57 +/- 101 ng/l, p = NS). CONCLUSIONS: Patients with chronic CAD exhibit much higher exercise releases of ANP and BNP when they are treated with beta-blockers. This enhanced secretion of potent vasodilating and natriuretic agents constitutes an original therapeutic mechanism for further protecting diseased hearts against stress.