ESPE Abstracts

Background: GLI2 is a transcription factor downstream in SH signaling, playing an early role in ventral forebrain and pituitary development. GLI2 mutations have been reported in patients with holoprosencephaly and/or congenital hypopituitarism, showing significant phenotypic variability. Here, we present a case involving a novel heterozygous missense mutation in GLI2.

Case Presentation: An Indian girl, adopted by an Italian family, presented with stunted growth at 2.7 years old. Her medical history revealed normal birth weight (4040g), a length of 49 cm, and a head circumference of 35 cm. Unfortunately, her gestational age at birth and delivery mode remain unknown. Before adoption, she underwent surgical correction for bilateral labiopalatoschisis in India at 1.5 years of age. At the age of 2.7, her height measured 72.2 cm (-5.4 SDS, according to the WHO growth chart), weight was 7.3 kg (-5.13 SDS), and head circumference was 44 cm (-2 SDS). Clinical examination revealed a central incisor, incomplete deciduous teeth eruption, right palpebral ptosis, and extreme joint laxity. Due to severe growth failure, she required hospitalization. Hypoglycemic crises occurred, associated with absent elevation of growth hormone (GH) and cortisol levels (glucose:28 mg/dL, GH:0.44 ng/dL, cortisol:6.8 mcg/dL). Mild hyponatremia (132mEq/L) was also noted. Suspecting a midline defect, intravenous fluid therapy and hydrocortisone were initiated. However, corticosteroid administration led to polyuria, progressing to clear central diabetes insipidus (CDI) a week after (urine output:2200mL, Na148mEq/mL, low urinary osmolarity). AVP replacement therapy (7.5μg three times a day) was started. Brain MRI revealed the classical triad of pituitary stalk interruption syndrome with absence of neurohypophysis. She subsequently received recombinant growth hormone therapy. After 2.4 years of follow-up, her height increased to 90.1 cm (-3.46 SDS), with a growth velocity of 9.4 cm per year. Her BMI was 14.5 kg/m² (-0.47 SDS). No further pituitary deficiency has developed so far.

Methods: NGS was performed for congenital hypopituitarism.

Results: A novel heterozygous GLI2 mutation was identified: c.596G>A,p.Gly199Asp; NM_001374353.1(exon 5). The variant is of uncertain significance (ClinVar), but showed moderate pathogenic potential (in-silico predictor metaRNN).

Conclusion: Our findings confirm the association of GLI2 haploinsufficiency with mild holoprosencephaly spectrum features, and characterize the phenotype of the missense mutation p.Gly199Asp. Our patient developed CDI, a feature sometimes associated with holoprosencephaly but not previously related to GLI2. The deficit was unveiled by glucocorticoid therapy. Therefore, attention should be paid when hypopituitarism is encountered as CDI may present on administration of glucocorticoid.