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.
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.
Authors: Hilana M Lewkowitz-Shpuntoff; Virginia A Hughes; Lacey Plummer; Margaret G Au; Richard L Doty; Stephanie B Seminara; Yee-Ming Chan; Nelly Pitteloud; William F Crowley; Ravikumar Balasubramanian Journal: J Clin Endocrinol Metab Date: 2011-11-09 Impact factor: 5.958
Authors: Magdalena Avbelj Stefanija; Marc Jeanpierre; Gerasimos P Sykiotis; Jacques Young; Richard Quinton; Ana Paula Abreu; Lacey Plummer; Margaret G Au; Ravikumar Balasubramanian; Andrew A Dwyer; Jose C Florez; Timothy Cheetham; Simon H Pearce; Radhika Purushothaman; Albert Schinzel; Michel Pugeat; Elka E Jacobson-Dickman; Svetlana Ten; Ana Claudia Latronico; James F Gusella; Catherine Dode; William F Crowley; Nelly Pitteloud Journal: Hum Mol Genet Date: 2012-07-05 Impact factor: 6.150
Authors: Cecilia Martin; Ravikumar Balasubramanian; Andrew A Dwyer; Margaret G Au; Yisrael Sidis; Ursula B Kaiser; Stephanie B Seminara; Nelly Pitteloud; Qun-Yong Zhou; William F Crowley Journal: Endocr Rev Date: 2010-10-29 Impact factor: 19.871
Authors: Yee-Ming Chan; Sarabeth Broder-Fingert; Sophia Paraschos; Risto Lapatto; Margaret Au; Virginia Hughes; Suzy D C Bianco; Le Min; Lacey Plummer; Felecia Cerrato; Adelaide De Guillebon; I-Hsuan Wu; Fazal Wahab; Andrew Dwyer; Susan Kirsch; Richard Quinton; Timothy Cheetham; Metin Ozata; Svetlana Ten; Jean-Pierre Chanoine; Nelly Pitteloud; Kathryn A Martin; Raphael Schiffmann; Hetty J Van der Kamp; Shahla Nader; Janet E Hall; Ursula B Kaiser; Stephanie B Seminara Journal: J Clin Endocrinol Metab Date: 2011-08-31 Impact factor: 5.958
Authors: Flavia Amanda Costa-Barbosa; Ravikumar Balasubramanian; Kimberly W Keefe; Natalie D Shaw; Nada Al-Tassan; Lacey Plummer; Andrew A Dwyer; Cassandra L Buck; Jin-Ho Choi; Stephanie B Seminara; Richard Quinton; Dorota Monies; Brian Meyer; Janet E Hall; Nelly Pitteloud; William F Crowley Journal: J Clin Endocrinol Metab Date: 2013-03-26 Impact factor: 5.958