Re-analysis of gene mutations found in pituitary stalk interruption syndrome and a new hypothesis on the etiology

Abstract

Background: Pituitary stalk interruption syndrome (PSIS) is a complex clinical syndrome characterized by varied pituitary hormone deficiencies, leading to severe manifestations across multiple systems. These include lifelong infertility, short stature, mental retardation, and potentially life-threatening pituitary crises if not promptly diagnosed and treated. Despite extensive research, the precise pathogenesis of PSIS remains unclear. Currently, there are two proposed theories regarding the pathogenic mechanisms: the genetic defect theory and the perinatal injury theory.

Methods: We systematically searched English databases (PubMed, Web of Science, Embase) and Chinese databases (CNKI, WanFang Med Online, Sinomed) up to February 24, 2023, to summarize studies on gene sequencing in PSIS patients. Enrichment analyses of reported mutated genes were subsequently performed using the Metascape platform.

Results: Our study included 37 articles. KEGG enrichment analysis revealed mutated genes were enriched in the Notch signaling pathway, Wnt signaling pathway, and Hedgehog signaling pathway. GO enrichment analysis demonstrated mutated genes were enriched in biological processes such as embryonic development, brain development, axon development and guidance, and development of other organs.

Conclusion: Based on our summary and analyses, we propose a new hypothesis: disruptions in normal embryonic development, partially stemming from the genetic background and/or specific gene mutations in individuals, may increase the likelihood of abnormal fetal deliveries, where different degrees of traction during delivery may lead to different levels of pituitary stalk interruption and posterior lobe ectopia. The clinical diversity observed in PSIS patients may result from a combination of genetic background, specific mutations, and variable degrees of traction during delivery.

Keywords: enrichment analysis; etiological hypothesis; gene sequencing; pituitary stalk interruption syndrome; traction during delivery.

Figure 1

Flow diagram of literature screening. For details, please refer to “2. Methods”.

Figure 2

Pathway and process enrichment analysis. (A) The bar graph displays enriched terms across input gene lists, colored by P value. (B) The network illustrates enriched terms colored by P value, with terms containing more genes typically having a more significant P value. (C) The network represents enriched terms colored by cluster ID, where nodes sharing the same cluster ID are generally close to each other. (D–G). The enrichment analysis results of the input genes in KEGG Pathways (D), GO Biological Processes (E), GO Cellular Components (F), and GO Molecular Functions (G) are visually depicted through the utilization of bubble charts.

Figure 3

Protein-protein interaction enrichment analysis. (A) The protein-protein interaction network illustrates the intricate patterns of interactions between proteins, aiding in our understanding of how proteins are interconnected and regulated within cellular biology processes. (B) The MCODE components are modular protein interaction clusters that have been pinpointed through the analysis of gene lists, facilitating the recognition of key gene sets that play crucial roles in biological processes.

Figure 4

A new etiological hypothesis of PSIS. (A–C) Pathogenic genetic defects were identified in only less than 5% of PSIS patients. In the existing reports, mutated genes in PSIS patients were associated with the development of the pituitary gland, hypothalamus, and the anterior or intermediate regions of the forebrain, which may increase the rate of perinatal adverse events such as breech presentation and neonatal distress. Compared with newborns who underwent normal delivery, newborns who experienced perinatal adverse events were more likely to suffer more injuries secondary to traction during childbirth. Different degrees of damage to the hypothalamic-pituitary region caused by traction may be an important factor for different locations of ectopia posterior lobe in PSIS patients. (D) MRI image of the normal hypothalamic-pituitary region. (E) Illustrative diagram corresponding to D. ME, median eminence; C, chiasm; PS, pituitary stalk; AP, anterior pituitary; PP, posterior pituitary. (F) The MRI image shows anterior pituitary hypoplasia, an invisible pituitary stalk, and ectopic location of the posterior pituitary gland near the pituitary fossa along the PS. (G) Illustrative diagram corresponding to (F). (H) The MRI image shows ectopic location of the posterior pituitary gland in the middle of PS. (I) Illustrative diagram corresponding to (H). (J) The MRI image shows anterior pituitary hypoplasia, an invisible pituitary stalk, and ectopic location of the posterior pituitary gland in the ME. (K) Illustrative diagram corresponding to (H). To obtain additional magnetic resonance images of pituitary posterior lobe ectopia in different locations, please refer to this review article (71).