Evidence that FGFR1 loss-of-function mutations may cause variable skeletal malformations in patients with Kallmann syndrome
Section snippets
INTRODUCTION
Kallmann syndrome (KS) associates congenital hypogonadotropic hypogonadism, responsible for the absence of sexual maturation at puberty or for partial puberty, associated with anosmia or hyposmia. Patients have low serum gonadotropin and sex steroid levels, and display hypoplasia or aplasia of the olfactory bulbs, together with normal pituitary and hypothalamus on MRI [1]. KS may occur in association with a variety of additional neurological (bimanual synkinesis, sensorineural hearing
MATERIALS AND METHODS
A cohort of 29 KS patients (24 males and 5 females) was screened for the presence of mutations in 5 of the currently known KS genes, i.e. KAL1, FGFR1, FGF8, PROKR2, PROK2. KS was diagnosed on the delayed puberty, defective sense of smell (anosmia or hyposmia), low serum levels of gonadotropins, low serum testosterone or estradiol concentrations, normal baseline levels of other anterior pituitary hormones, and normal MR imaging of the hypothalamic – pituitary region. Karyotype analysis did not
RESULTS
A clinical description of the 5 KS patients who carry mutations in FGFR1 is provided below, and the main features are summarized in Tab. 1.
DISCUSSION
We report on 5 KS patients who carry different, presumably pathogenic sequence variants in FGFR1, all leading to single amino-acid changes in the protein sequence (missense mutations). In 4 patients, the mutations were found in heterozygous state, and the fact that they were not detected in the parents’ genomic DNAs (de novo mutations) is strong evidence of their pathogenic effect. The fifth patient is homozygous for the p.Ala167Ser mutation. To our knowledge, this is the only FGFR1 pathogenic
CONCLUSIONS
In conclusion, we report here skeletal abnormalities of the spine and the limb extremities in three out of five KS patients carrying mutations in FGFR1. A systematic search for skeletal anomalies in KS patients with FGFR1 mutations would be useful to determine the prevalence of such anomalies. Conversely, the presence of these malformations in KS patients could direct genetic screening towards FGFR1. This study brings evidence of the involvement of FGF/FGFR1 signaling pathways in skeletal
ACKNOWLEDGEMENTS
We thank Dr Catherine Dode, Inserm U1016, Department of Genetics and Development, Cochin Institute, Paris, France, for completing genetics studies, and Dr Barbara Goulet-Salmon, Alençon Hospital, F-61000, France for her assistance in this study.
The authors declare no conflict of interest.
This work was supported in part, by a grant from “delegation de la recherche clinique” of Caen to ML Kottler: APR2001.
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