ESPE Abstracts (2018) 89 P-P2-266

A Novel FGFR1 Mutation in Kallmann Syndrome with Growth Hormone Deficiency

Gianluca Tornesea, Maria Chiara Pellegrina, Matteo Pavana, Elena Faleschinia & Egidio Barbia,b


aIRCCS Burlo Garofolo, Trieste, Italy; bUniversity of Trieste, Trieste, Italy


Background: Kallmann syndrome (KS) is a genetic disorder, mainly characterized by the association of anosmia (due to hypo/aplasia of the olfactory bulbs) and hypogonadotropic hypogonadism (due to GnRH deficiency). Both partial or complete forms are described. Other features (skeletal and renal malformations, deafness, bimanual synkinesis) can be variably associated. Behind this phenotypic heterogeneity, there is a considerable complexity of genetic mutations. KAL1, FGFR1, PROKR2, PROK2, CHD7, FGF8 are the principal genes involved, accounting up to 35% of KS cases.

Case presentation: A 4-years old boy presented to our Pediatric Endocrinology Unit for deceleration in growth velocity in the previous two years (−1.8 S.D.), with normal height (−0.1 S.D., according to Italian curves), weight and body proportion. He was prepubertal, without micropenis and cryptorchidism. Past medical history was unremarkable, he was born at term from non-consanguineous parents. His father was affected by KS, clinically diagnosed at the age of 14 because of anosmia and pubertal delay. A diagnosis of GH deficiency was confirmed by two stimulation tests (peak 5.74 ng/ml and 7.61 ng/ml, respectively), associated to low level of IGF-1 (25.7 ng/ml, nv 50–286). Brain MRI showed no morphological alteration of pituitary gland but, unexpectedly, highlighted olfactory bulbs hypoplasia. Anosmia was further confirmed by the olfactory test. Alteration of kidneys, limbs movement and hearing were excluded. Genetic investigation showed a heterozygous mutation in the FGFR1 gene (c.976C→G), both in the proband and his father, but not in his grandparents. This mutation has neither been previously reported by literature, nor it is comprised by the Single Nucleotide Polymorphisms (SNPs) database. Therefore, it is a de novo mutation, who passed from the father to the child. The pathogenicity was evaluated with prediction software (positive predictive value 0.99 and 0.89 of Mutation Tester and PoliPhen2, respectively). GH replacement therapy was started, with a good clinical response. At 9 years of age, he is still prepuberal.

Conclusions: Despite phenotypic variability, KS has been rarely associated to GH deficiency and short stature. KS is usually suspected in the pubertal period as a result of primary or secondary signs of hypogonadism, and not as a result of poor height growth. FGFR1 gene has been independently associated both to KS and to pituitary dysfunction. This novel mutation of FGFR1 might determine the concurrence of these both clinical situations.

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