ESPE Abstracts

Background: Genetic variants are identified in a small proportion (~10%) of patients with Congenital Hypopituitarism (CH), with variable associated phenotypes. We aimed to phenotypically characterise a large cohort of patients with genetically proven CH.

Patients and methods: 1684 CH patients were screened (Sanger or whole exome sequencing) over a 20-year period (1998-2018) for mutations in genes regulating pituitary development. The cohort included patients with: Multiple Pituitary Hormone Deficiency (MPHD) (n=621), Isolated Growth Hormone Deficiency (IGHD) (n=414), Holoprosencephaly (HPE) (n=64), Septo-Optic Dysplasia (SOD) (n=526) and Severe Eye Defects (SED) (n=59). Retrospective clinical/neuroradiological data were collected.

Results: Genetic variants were identified in 146/1684 patients (8.7%): 54/621 (8.7%) MPHD, 59/414 (14.3%) IGHD, 3/64 (4.7%) HPE, 14/526 (2.7%) SOD, 16/59 (27.1%) SED. The most frequent genetic variants identified in different groups were: PROP1 and POU1F1/PIT1 for MPHD; GH1, GHRHR and GLI2 for IGHD; PROKR2 for SOD; SOX2 for SED; and SHH for HPE. Pituitary deficits were present in 140/146 (95.9%) patients. The majority had GHD, except for SOX2 mutations (isolated gonadotrophin deficiency). Other pituitary deficiencies were more variable. Stimulated peak GH concentrations were lowest in those patients with POU1F1/PIT1 (0.30±0.21 µg/L), LHX3 (0.71±0.53 µg/L), GHRHR (0.73±0.76 µg/L), PROP1 (0.80±0.79 µg/L), and SOX3 (0.88±1.03 µg/L) mutations. Hypothalamo-pituitary abnormalities were reported on MRI in 98/124 (79%) patients, the most prevalent being a small anterior pituitary across all groups. 4/15 (26.7%) patients with PROP1 and 1/2 patients with an FGF8 mutation had anterior pituitary enlargement; ectopic posterior pituitary was detected in 6/11 (54.5%) PROKR2, 3/8 (37.5%) GLI2, 4/5 (80%) SOX3, 3/6 (50%) HESX1, 3/4 (75%) LHX4 and 4/4 (100%) OTX2 variants.

Midline forebrain developmental defects were associated with PROKR2, FGF8, KAL1, TCF7L1, SOX2, and SHH mutations, whilst other brain abnormalities (eg. hippocampal/cerebellar abnormalities, hypothalamic hamartoma) were identified in patients with SOX2, PROKR2, OTX2, GH1, SOX3, FGF8 variants. Neurological abnormalities (developmental delay, autistic spectrum disorder, epilepsy) were prevalent in patients with SOX2, PROKR2, OTX2, SHH, TCF7L1, FGF8, and LHX3 variants. Skeletal malformations and deafness were described in all patients with an LHX3 mutation, whilst eye defects were present in all patients with SOX2 variants.

Conclusions: Heterogeneous phenotypes are associated with CH. However distinctive hypothalamo-pituitary and extra-pituitary features in these patients can aid in genotype prediction. Due to the rapidly increasing number of hypothalamo-pituitary associated genes, next generation sequencing has replaced Sanger sequencing enabling a fast and thorough analysis of patient genomes to identify novel mutations and candidate genes.