ESPE Abstracts

Background: Congenital hypopituitarism (CH) genetics is highly heterogeneous. The massive use of NGS identified at least 21 desease causing genes. Not fully understood inheritance mechanism, incomplete penetrance and variable expressivity explain the complexity of phenotype-genotype correlations. To further complicate the scenario, the co-occurence of more than one desease-causing genes variants can geopardize the phenotype. Herein, we report the heterogeneous genotype and phenotype retrieved in 3 patients with growth deficiency (GHD) belonging to 2 distinct family. All patients carried a novel identical mutations in LHX4 gene, whose disruption causes CPDH4. Besides, a GLI3 variant in patient-1 and IGF1R variant family B was identified.

Case presentation: Patient-1(family A) presented at 17months of age in suspicion of short stature(SS) genetically due. His height was -2SD, BMI and head circumference (HC) were normal, facies composita and brilliant neurodevelopment. Hormonal data confirmed diagnosis of GHD and central hypothyroidism. Brain RMI revealed important radiological abnormalities: severe pituitary hypoplasia, neurohypophisis ectopia and stalk interruption. Patient responded adequately to replacement therapies. Siblings of family B, patient-2 and 3, aged 8.3 years and 9 months old respectively, were referred for poor growth since birth and familial SS. They were born SGA. Clinical examination revealed severe SS (-6.18SD and -4.11SD for patient-2 and 3 prespectively). Normal BMI and adequate neurodevelopment. Patient-3, also presented small HC (-1.56SD) and hypotelorism. Hormonal data confirmed GHD and, for patient-2, hypothyroidism. Brain MRI documented in both: pituitary hypoplasia, thin stalk and ectopic neurohypophisis. Patient-3 also had olfactory bulb and tract hypoplasia-agenesia. They responded poorly to rGH treatment.

Genetics: exome sequencing highlighted the unreported LHX4 variant(c. 481C>G) in heterozygous state in all patients. In patient-1, the variant was paternally inherited. The father presented short stature and low IGF1 levels. Family B patients inherited from their healthy mother. Brain scan revealed minor pituitary abnormality in parents with LHX4 mutation. Additionally, another heterozygotic gene variant was present: family A proband carried a maternally-inherited GLI3 mutation (c.250C>A), while family B patients shared a paternally-inherited IGF1R mutation(c.166G>A).

Conclusion: CH has a complex and in some cases polygenic inheritance. In family A, the association of GLI3 and LHX4 variants, genes involved in midline embriology, caused a severier radiological abnormalities in patient-1 compared to his parents, while IGF1R mutation in family B explains their IUGR and poor treatment response.