ESPE Abstracts

Background: Heterozygous loss-of-function variants of fibroblast growth factor receptor 1 (FGFR1) are genetic causes of Combined Pituitary Hormone Deficiency (CPHD), Kallmann syndrome (KS) with anosmia/iposmia, Congenital Hypogonadotropic Hypogonadism (CHH) with normosmia and Septo-Optic Dysplasia. It is well-known that these variants are the main genetic factor underlying the development of CHH and KS; however, they have only occasionally been identified in CPHD.

Case presentation: A 14-year-old boy was admitted to Outpatient Clinic of Pediatric Endocrinology for short stature (-2.6 SDS) and pubertal delay. He had a personal history of cleft lip and palate and cryptorchidism surgically corrected during childhood. During follow-up he had significantly deficient height growth rate (1.4 cm/year) and failure to spontaneous onset of puberty despite evidently puberogenic bone age (14 years). In consideration of the abovementioned findings, the patient underwent endocrinological investigation, including endocrine dynamic function test, that documented a growth hormone deficiency and hypogonadotropic hypogonadism (HH). The other pituitary tropins were within normal range. Brain MRI delineated a complex midline and maxillofacial bones malformation, 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. The pituitary gland was normal and the pituitary stalk in axis. Despite the complex alteration affecting the olfactory structures, the patient presented normosmia. The patient underwent array-CGH, which resulted negative for microduplications or microdeletions, and trio exome sequencing. The latter identified a de novo heterozygous missense variant c.2002G>A in FGFR1 gene, that determines the aminoacidic change p.Glu668Lys. This missense variant is classified as pathogenic (class 5 according to ACMG criteria) and is associated with autosomal dominant HH. Since the age of 15 years the patient was treated with daily growth hormone therapy, which resulted in significant height recovery (from -2.6 SDS to -1.66 SDS), and testosterone, which promoted the appearance of secondary sexual characteristics. GnRh and gonadotropin therapy was considered to promote increased testicular volume and future fertility.

Conclusion: This case highlights the role of missense variants of FGFR1 in the development of combined pituitary hormone deficiency associated with complex brain malformation even without anosmia. In the diagnostic workup of HH, the role of comprehensive pituitary function study, brain MRI, and genetic analysis is crucial in clarifying the etiology of HH and any possible associated comorbidities.