Phenotypic heterogeneity in pediatric pituitary stalk interruption syndrome: greater disease burden in the metabolic-onset phenotype

Pituitary stalk interruption syndrome (PSIS) is a rare congenital hypothalamic-pituitary disorder with marked clinical heterogeneity. Whether different presenting phenotypes reflect variations in disease burden and neurodevelopmental outcomes remains unclear. This study aimed to characterize distinct presenting phenotypes of children with PSIS and compare their diagnostic trajectories, endocrine and structural disease burden, and neurodevelopmental outcomes.

In this single-center retrospective study, 31 magnetic resonance imaging (MRI)-confirmed children with PSIS were classified into a systemic-onset phenotype (n=10; hypoglycemia, cholestasis, micropenis, or adrenal crisis) and a growth-predominant phenotype (n=21; short stature or growth deceleration). Clinical characteristics, pituitary hormone deficiency profiles at diagnosis and during follow-up, MRI findings, and neurodevelopmental outcomes were compared. Exploratory Spearman analyses examined potential associations between baseline clinical and endocrine characteristics and general quotient (GQ).

The systemic-onset phenotype showed earlier symptom onset (0.07±0.04 vs. 2.68±0.73 years, P<0.001) but longer diagnostic lag (4.75±1.26 vs. 2.93±1.02 years, P=0.001). At diagnosis, the systemic-onset phenotype showed higher proportions of adrenocorticotropic hormone (ACTH) deficiency (80.0% vs. 33.3%, P=0.02) and luteinizing hormone/follicle-stimulating hormone (LH/FSH) deficiency (60.0% vs. 9.5%, P=0.006), a greater number of deficient pituitary axes, and lower anterior pituitary height after adjustment for age at MRI evaluation. Isolated growth hormone deficiency was present in 8 of 21 (38.1%) children with the growth-predominant phenotype but in none of those with the systemic-onset phenotype. During follow-up, at least one additional pituitary hormone deficiency was newly identified in 30.0% and 38.1% of the systemic-onset and growth-predominant groups, respectively (P>0.99), while the systemic-onset phenotype retained a greater number of deficient pituitary axes at the latest assessment (P=0.001). Neurodevelopmental outcomes were poorer, with lower GQ (P=0.007) and higher prevalence of intellectual disability (30.0% vs. 0%, P=0.03). Exploratory analyses suggested potential relationships between lower GQ and longer diagnostic lag, lower free thyroxine (FT4), lower basal cortisol, lower minimum blood glucose, and a greater number of deficient pituitary axes; these associations were exploratory and should not be interpreted causally.

The systemic-onset phenotype was associated with greater pituitary hormone deficiency burden at diagnosis, longer diagnostic lag, and poorer neurodevelopmental outcomes during follow-up. Initial clinical phenotype may provide a useful framework for early recognition and risk assessment, while the identification of additional pituitary hormone deficiencies during follow-up supports continued endocrine surveillance in both phenotypes.