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This version published online on December 21, 2004
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1361
A more recent version of this article appeared on March 1, 2005
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Submitted on July 16, 2004
Accepted on December 1, 2004

REVERSIBLE KALLMANN SYNDROME, DELAYED PUBERTY, AND ISOLATED ANOSMIA OCCURRING IN A SINGLE FAMILY WITH A MUTATION IN THE FGFR1 GENE

Nelly Pitteloud*, James S. Acierno jr., Astrid U. Meysing, Andrew A. Dwyer, Frances J. Hayes, and William F Crowley jr

Reproductive Endocrine Unit of the Dept. of Medicine & National Center for Infertility Research, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114

* To whom correspondence should be addressed. E-mail: npitteloud{at}partners.org.

Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder. Recently, loss-of-function mutations in the fibroblast growth factor receptor 1 (FGFR1) gene have been shown to cause autosomal dominant (AD) KS. To date, the detailed reproductive phenotype of KS associated with mutations in the FGFR1 has yet to be described.

We report a kindred comprising a male proband with Kallmann syndrome and spontaneous reversibility, whose mother had delayed puberty, and maternal grandfather isolated anosmia. The proband presented at age 18 with KS and was subsequently treated with testosterone (T) therapy. Upon discontinuation of T therapy, he recovered from his hypogonadotropic hypogonadism (HH) as evidenced by normal LH secretion pattern, sustained normal serum T levels, and active spermatogenesis. The three members of this single family harbor the same FGFR1 mutation (Arg622X) in the tyrosine kinase domain.

This report demonstrates: 1) the first genetic cause of the rare variant of reversible KS; 2) the reversal of HH in a proband carrying an FGFR1 mutation suggests a role of FGFR1 beyond embryonic GnRH neuron migration; and 3) that a loss-of-function mutation in the FGFR1 gene causing delayed puberty.
Key words: FGFR1 mutation • Kallmann syndrome • idiopathic hypogonadotropic hypogonadism • reversal • delayed puberty




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