Clinical and genetic characteristics of combined pituitary hormone deficiency caused by aberrations in the PROP1 gene

Background: One of the most common causes of congenital hypopituitarism is the occurrence of inactivating variant aberrations in the PROP1 gene. Encoding the transcription factor of the same name, PROP1 is a key regulator of the differentiation of pluripotent cells of the anterior pituitary gland into individual cell lines with characteristic secretory profiles. Homozygous and compound heterozygous variants of the PROP1 gene lead to the development of combined pituitary hormone deficiency, characterized by deficiency of somatotropic hormone (STH), thyroid-stimulating hormone (TSH), prolactin (PRL), and gonadotropic hormones. Deficiency of adrenocorticotropic hormone (ACTH) is a more variable symptom, in rare cases it can develop in childhood, more often in adolescence and older age, or it can be absent throughout the patient’s life. In 1998, cDNA of the human PROP1 gene was cloned by P. Duquesnoy et al. In the same year, O.V. Fofanova, together with S. Yamashita and other Japanese scientists were among the first to identify defects in the PROP1 genes in patients with multiple pituitary hormone deficiency. More and more data concerning the study of this problem are appearing in the foreign literature. In the domestic literature, there are descriptions of a small number of groups of patients with defects in the PROP1 gene. This work is aimed at expanding the understanding of the etiology, pathogenesis and characteristics of this rare disease.

Objective. Clinical, hormonal and molecular genetic characteristics of cases of monogenic hypopituitarism associated with variants in the PROP1 gene.

Materials and methods: A single-center, non-interventional, cross-sectional, non-comparative study was conducted, which included 54 patients with hypopituitarism associated with a variant substitution in the PROP1 gene. All patients underwent a comprehensive examination, including laboratory and instrumental diagnostic methods and NGS (next-generation sequencing).

Results: 54 children (30 girls, 24 boys) with variant substitutions in the PROP1 gene were examined. The frequency of variant substitutions in the PROP1 gene among children with monogenic hypopituitarism in the Russian population was 44% (95% CI: 34.5–52.7). All identified variants in the PROP1 gene were previously described in the world literature as pathogenic. The most common defect was the compound heterozygous variant c.301_302del/c.150del – detected in 23 (42.5%) cases. The age at the time of hypopituitarism diagnosis was 4.5 (3.0–5.6) years. All children had growth hormone deficiency and secondary hypothyroidism. In a smaller number of cases, hypopituitarism included corticotropic hormone deficiency (40.7%) and hypoprolactinemia (16.6%). Secondary hypogonadism was diagnosed in all children who reached puberty (n=17). According to the results of magnetic resonance imaging of the brain, changes typical for a defect in the PROP1 gene (hyperplasia of the pituitary gland and total changes in the structure of the pituitary gland) were detected in 46% of cases, pituitary hypoplasia – in 26% of cases.

Conclusion: The largest domestic study on the frequency of PROP1-associated hypopituitarism was conducted. In patients with the same aberration, the age and sequence of manifestation of tropic deficiencies can vary significantly. The high probability of developing secondary hypocorticism in this genetic defect postulates the extreme importance of monitoring patients throughout their lives, including the need for regular monitoring of serum cortisol levels.