A Novel Missense Variant in LHX4 in Three Children with Multiple Pituitary Hormone Deficiency Belonging to Two Unrelated Families and Contribution of Additional GLI2 and IGFR1 Variant.

Background: Multiple genes can disrupt hypothalamic-pituitary axis development, causing multiple pituitary hormone deficiencies (MPHD). Despite advances in next-generation sequencing (NGS) identifying over 30 key genes, 85% of cases remain unsolved, indicating complex genotype-phenotype correlations and variable inheritance patterns.

Objective: This study aimed to identify the MPHD genetics in three probands from two unrelated families.

Methods: Family A had one affected child, while Family B had two affected siblings. All probands exhibited poor growth since birth, and family B's probands were born small for gestational age. Growth hormone deficiency was confirmed in all subjects. Family B's probands responded poorly to growth hormone treatment compared to the first patient. Furthermore, Family A's proband and Family B's younger sibling developed central hypothyroidism, while Family B's older sibling presented hypogonadotropic hypogonadism. Brain magnetic resonance imaging (MRI) revealed pituitary hypoplasia, ectopic posterior pituitary gland, and small sella turcica in all probands. Patients and their available relatives underwent NGS.

Results: NGS identified the same novel and likely pathogenic LHX4 variant (c.481C>G) in all probands despite the families being unrelated. Additionally, Family A's proband carried a GLI2 variant (c.2105C>A), and Family B's probands carried an IGF1R variant (c.166G>A), both interpreted as being of uncertain significance.

Conclusions: This study confirms that heterozygous pathogenic variants of LHX4 can cause MPHD associated with a specific neuroradiological triad of abnormalities despite incomplete penetrance and variable phenotype. Moreover, the co-occurrence of the other two gene variants was debated. The IGF1R variant could explain the unusually poor response to growth hormone therapy in Family B, suggesting an oligogenic mechanism underlying the phenotype.