ESPE Abstracts

Introduction: Primary multiple pituitary hormone deficiency (MPHD) is caused by impaired development of the pituitary gland during the intrauterine period. Pathogenic variants in numerous genes affecting pituitary morphogenesis or differentiation have been proven to cause MPHD. However, in most people, genetic examination still fails to bring a conclusive finding explaining the cause of MPHD. The aim of our study was to identify the genetic aetiology of MPHD using next-generation sequencing (NGS) in a single-centre cohort of children treated with growth hormone (GH).

Patients and Methods: Currently, a total of 38 children with primary MPHD (GH deficiency combined with the impaired secretion of at least one other pituitary hormone) are treated with GH in our centre. Their median age is 12.7 years (IQR 8.2 to 14.5 years), height prior to GH treatment initiation -3.0 SD (-4.0 to -1.8 SD), pre-treatment IGF-1 -1.8 SD (-2.0 to -1.7 SD) and maximal stimulated GH 1.4 mg/L (0.4 to 3.4 mg/L). Out of them, 31 (82%) have central hypothyroidism, 29 (76%) central hypocortisolism, 6 (16%) hypogonadotropic hypogonadism diagnosed so far and 3 (8%) central diabetes insipidus. The brain MRI detected a midline defect in 27/38 (71%) children, 15 children (39%) had psychomotor retardation and 15 (13%) epilepsy. Children with a clinical suspicion of specific genetic disorder underwent standard genetic examination prior to the study. The children with unknown genetic cause were examined by targeted NGS panel containing 398 genes known to influence growth. All the variants with a potential clinical significance were evaluated by the American College of Medical Genetics standards.

Results: Causative genetic aetiology was confirmed in 10/38 (26%) children with MPHD. Out of these, 6 children carried causative genetic variant in genes known to play an important role in pituitary development and are known to cause MPHD (OTX2 [2], PROP1, POU1F1, GLI2, TBX3). The remaining 4 children had a genetic variant corresponding with their complex syndromic phenotype, but the genes have not been described with MPHD yet (PMM2, GNAO1, FLNB and a complex chromosomal aberration). Moreover, in an additional 6/38 (16%) children with MPHD we found a variant of unknown significance (GLI2 [2], FBN1 [2], LZTR1, FLNB) potentially causing MPHD.

Conclusion: Genetic aetiology of MPHD is complex. In substantial number of cases, the mechanisms leading to MPHD remain to be elucidated. Our study suggests some new candidate genes potentially responsible for MPHD.