Evidence that FGFR1 loss-of-function mutations may cause variable skeletal malformations in patients with Kallmann syndrome

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ABSTRACT

Purpose

Loss-of-function mutations in FGFR1 have been identified in approximately 10% of the Kallmann syndrome (KS) patients. Previous reports have focused mainly on olfactory, reproductive, and some other features such as cleft lip/palate and dental agenesis. Given the ubiquitous expression of FGFR1 during development, other abnormal phenotypes might, however, have been overlooked in these patients. Here, we demonstrate skeletal phenotypic characterization of patients presented with KS and FGFR1 mutations.

Material and Methods

Using the Sanger DNA sequencing technique a cohort of 29 KS patients was screened.

Results

Here, we report on 5 KS patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Three patients presented with skeletal abnormalities, i.e. spine (hemivertebra and butterfly vertebra) and limb (oligodactyly of the feet, fusion of the 4th and 5th metacarpal bones) malformations in two patients and one patient, respectively. The hand phenotype found in the patient cannot be thought of as a counter-type of the hand phenotype resulting from FGFR1 gain-of-function mutations. The skeletal anomalies identified in the 3 KS patients are close to those observed in Fgfr1 conditional knockout mice.

Conclusions

This study demonstrates that FGFR1 loss-of-function mutations can be associated with skeletal abnormalities also in humans. Further investigations in KS patients who carry FGFR1 mutations are needed to evaluate the prevalence of skeletal defects in this genetic form of KS. Conversely, the presence of bone malformations in a KS patient should direct the geneticist towards a search for mutations in FGFR1.

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.

REFERENCES (58)

  • HJ Im et al.

    Basic fibroblast growth factor stimulates matrix metalloproteinase-13 via the molecular cross-talk between the mitogen-activated protein kinases and protein kinase Cdelta pathways in human adult articular chondrocytes

    J Biol Chem.

    (2007 Apr 13)
  • JP Hardelin et al.

    The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al.

    Sex Dev.

    (2008)
  • JD Wegenke et al.

    Familial Kallmann syndrome with unilateral renal aplasia

    Clin Genet.

    (1975 May-Jun)
  • B Conrad et al.

    Hereditary bimanual synkinesis combined with hypogonadotropic hypogonadism and anosmia in four brothers

    J Neurol.

    (1978 Aug 25)
  • JD Schwankhaus et al.

    Neurologic findings in men with isolated hypogonadotropic hypogonadism

    NeUrology

    (1989 Feb)
  • J Hill et al.

    Audiological, vestibular and radiological abnormalities in Kallman's syndrome

    J Laryngol Otol.

    (1992 Jun)
  • F de Zegher et al.

    Kallmann syndrome and delayed puberty associated with agenesis of lateral maxillary incisors

    J Craniofac Genet Dev Biol.

    (1995 Apr-Jun)
  • K Mølsted et al.

    Craniofacial morphology in patients with Kallmann's syndrome with and without cleft lip and palate

    Cleft Palate Craniofac J.

    (1997 Sep)
  • B Franco et al.

    A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules

    Nature

    (1991 Oct 10)
  • JP Hardelin et al.

    X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene

    Proc Natl Acad Sci U S A.

    (1992 Sep 1)
  • C Dodé et al.

    Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

    Nat Genet.

    (2003 Apr)
  • J Falardeau et al.

    Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice

    J Clin Invest.

    (2008 Aug)
  • C Dodé et al.

    Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2

    PLoS Genet.

    (2006 Oct 20)
  • J Tornberg et al.

    Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

    Proc Natl Acad Sci U S A.

    (2011 Jul 12)
  • JP Hardelin et al.

    Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome

    Dev Dyn.

    (1999 May)
  • J Albuisson et al.

    Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2)

    Hum Mutat.

    (2005 Jan)
  • N Sato et al.

    Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients

    J Clin Endocrinol Metab.

    (2004 Mar)
  • R Quinton et al.

    Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization

    Clin Endocrinol (Oxf).

    (2001 Aug)
  • C Dodé et al.

    Kallmann syndrome: fibroblast growth factor signaling insufficiency?

    J Mol Med.

    (2004 Nov)
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