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A Mutation in the Fibroblast Growth Factor Receptor 1 Gene Causes Fully Penetrant Normosmic Isolated Hypogonadotropic Hypogonadism

Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology (N.X., Y.Q., S.P.T.T., P.G.M., L.C.L.), Developmental Neurobiology Program, The Institute of Molecular Medicine and Genetics (N.X., Y.Q., L.C.L.), The Neuroscience Program (L.C.L.), The Medical College of Georgia, Augusta, Georgia 30912; and Department of Obstetrics and Gynecology (R.H.R.), Section of Reproductive Endocrinology and Infertility, Dartmouth Medical School, Lebanon, New Hampshire 03755

Address all correspondence and requests for reprints to: Lawrence C. Layman, M.D., Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, The Medical College of Georgia, 1120 15th Street, Augusta, Georgia 30912-3360. E-mail: Llayman{at}mcg.edu.

Context: Kallmann syndrome (KS) consists of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia/hyposmia. Currently, the fibroblast growth factor receptor 1 (FGFR1) gene is the only known autosomal dominant cause of KS, which is also associated with synkinesia, midfacial defects, and dental agenesis.

Objective: Mutations in FGFR1 typically demonstrate reduced penetrance, variable expressivity, and until recently have been exclusively identified in families with anosmia. The purpose of this study was to determine whether FGFR1 mutations were present in a unique family with autosomal dominant, fully penetrant, normosmic IHH.

Design: The study is a review of detailed clinical findings, dynamic endocrine studies, and performance of a molecular analysis of the FGFR1 gene.

Setting: The study was carried out in an academic medical center.

Patients: All four affected individuals have complete IHH with full penetrance but no anosmia/hyposmia, and they have none of the FGFR1-associated anomalies. In addition, no other family member has anosmia.

Inverventions: Interventions included detailed phenotype characterization including history, physical exam, smell testing, dynamic pituitary testing, brain imaging, and molecular analysis.

Main Outcome Measures: Outcome was measured by the determination of the severity of IHH, olfactory function, and sequence of the FGFR1 gene.

Results: The same heterozygous nonsense mutation, Arg622X, was present in all four affected members, but not in three unaffected members or 100 controls. The mutation is predicted to encode a truncated protein or result in nonsense-mediated decay.

Conclusions: Our findings indicate that mutations in the FGFR1 gene can cause normosmic, fully penetrant, complete IHH with little or no variable expressivity, and without the other FGFR1-associated anomalies typically found in KS.

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				T. Raivio, Y. Sidis, L. Plummer, H. Chen, J. Ma, A. Mukherjee, E. Jacobson-Dickman, R. Quinton, G. Van Vliet, H. Lavoie, et al. Impaired Fibroblast Growth Factor Receptor 1 Signaling as a Cause of Normosmic Idiopathic Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4380 - 4390. [Abstract] [Full Text] [PDF]