ESPE Abstracts

Background: Congenital hypopituitarism (CH) refers to a deficiency of one or more pituitary hormones resulting from variants in genes encoding transcription factors for pituitary development. CH cases are mostly sporadic but 5-30% can be familial. Genetic etiology is not determined in most cases. The aim of our study was to evaluate the genetic features of CH using different molecular and/or molecular cytogenetic techniques.

Subjects and Methods: The data of 98 patients (34 girls) from 90 unrelated families were evaluated. Next-generation sequencing(NGS), multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) were used. MLPA (Probemix P216 GHD mix-1: GH1, LHX4, POU1F1, HESX1, PROP1, GHRHR, LHX3) (MRC Holland Amsterdam, Netherlands) was used. Clinical Exome Sequencing (CES) was performed using SOPHIA Clinical Exome Solution V2 (Boston, USA) via the Illumina Nextseq 550 platform (San Diego, CA, USA). Segregation analyses were performed.

Results: The median age at presentation was 6.6 years (range 7 days – 17.9 years). The mean gestation age was 37.8±2.8 weeks. Birthweight SDS was -0.3±1.4, and the SGA ratio was 12.8%. Consaguinity rate was %48.0. The neonatal jaundice and hypoglycemia ratio was 51.1% and 13.3%, respectively. Micropenis was detected in 19.9%, and cryptorchidism in 27.6%. At admission, height and BMI were -2.9±2.3 SD (target height -1.0±0.9 SD) and -0.3±1.5 SDS, respectively. Pituitary hormone deficiency rates were 95.9% for growth hormone (GH), 75.5% for TSH, 43.0% for ACTH, 34.7% for gonadotropin, 23.5% for prolactin, and 15.3% for AVP, during follow-up. Anomaly (agenesis, hypoplasia, and/or ectopic neurohypophysis) rate was 69.8% in pituitary MRI. Molecular genetic etiology was determined in 21.5% of families. Pathogenic variants were detected in PROP1 (7 cases from 3 families), POU1F1 (6 cases from 4 families), GLI2 (n=2), FOXA2 (n=2), LHX3 (n=1), LHX4 (n=1), and WDR11 (n=1) genes. In two cases CMA provided a definitive diagnosis (FOXA2 and LHX4) and MLPA (PROP1) in three cases. In one case with Cantu syndrome and CH, a previously reported variant in the KCNJ8 gene was detected. CES revealed pathogenic variants in other genes (PDE11A, KMT2A, H1-4, HUWE1) that are not yet associated with CH but have a known association with certain diseases. In one case, further analyses are proceeding on the candidate gene.

Conclusion: The molecular etiology was identified in 21.5% of our cohort. This low rate suggests that there may be many unknown molecular pathways that contribute to the complexity of pituitary development.