Combined pituitary hormone deficiency caused by a missense de novo variant in FGFR1

Heterozygous loss-of-function variants of fibroblast growth factor receptor 1 (FGFR1) are associated with Kallmann syndrome (KS) with anosmia/hyposmia, Congenital Hypogonadotropic Hypogonadism (CHH) with normosmia and Septo-Optic Dysplasia (SOD) and only occasionally with Combined Pituitary Hormone Deficiency (CPHD).We report the case of a 14-year-old boy who came to our attention for short stature and pubertal delay. The patient had a medical history of cleft lip and cryptorchidism, surgically corrected during childhood.Endocrinological investigation, including endocrine dynamic function test, documented a growth hormone deficiency and hypogonadotropic hypogonadism (HH), while the other pituitary tropin hormones were within normal range. Brain magnetic resonance imaging revealed a complex malformation of the midline and maxillofacial bones, with hypoplastic olfactory sulci, caudal dislocation of the fronto-basal cortical gyri, impaired cranio-caudal development of the nasal pits, nasal septal deviation, defect of the alveolar process of the maxillary bone, maxillary and frontal sinuses hypoplasia and one palatalized supernumerary tooth. Nevertheless, pituitary gland was normal and the pituitary stalk was in axis. Despite, these radiological findings no anosmia was reported. Trio exome sequencing analysis identified a de novo heterozygous missense variant c.2002GA in FGFR1 gene, that determines the aminoacidic change p. Glu668Lys, confirming the diagnosis of CPHD.Recombinant growth hormone and testosterone therapies were started, resulting in significant height recovery and in the development of secondary sexual characteristics.In conclusion, the comprehensive study of pituitary function, brain MRI and genetic analysis are crucial in the diagnostic work-up of HH in order to clarify its etiology and any associated comorbidities.