Pituitary stalk interruption syndrome: phenotype, predictors, and pathophysiology of perinatal events

Abstract

Purpose: There is limited data regarding Pituitary Stalk Interruption Syndrome (PSIS) from India. Moreover, the pathophysiological link between perinatal events and PSIS is unclear. We aim to elucidate the predictors of PSIS among patients with growth hormone de ciency (GHD) and perinatal events in PSIS by comparing cohorts of PSIS and genetically proven GHD without PSIS.Methods: Among 179 GHD patients, 56 PSIS and 70 genetically positive GHD (52-GHRHR, 15-POU1F1, and 3-PROP1) patients were included. Perinatal events, clinical anomalies, pituitary hormone de ciency, and imaging ndings were recorded. We compared subgroup of PSIS-isolated GHD (PSIS-IGHD) with GHRHR-IGHD and subgroup of PSIS-combined pituitary hormone de ciency (PSIS-CPHD) with POU1F1/PROP1-CPHD.Results: PSIS patients (45 males, median age: 12.5 years) most commonly presented with short stature. At last follow up (median age: 17.35 years), gonadal (during pubertal-age), thyroid and cortisol axes were affected in 81.6%, 62.5%, and 62.5%. 10/13 (77%) of PSIS children with initial IGHD diagnosis manifested hypogonadism during pubertal age. Male predominance, sporadic presentation, clinical anomalies were signi cantly higher in both PSIS subgroups than the respective genetic subgroups. Breech presentation was higher in PSIS-CPHD than POU1F1/PROP1-CPHD (44.4% vs 5.5%, p=0.004). Neonatal hypoglycemia (22% vs. 0%, p=0.05) and jaundice (42 vs. 5%, p=0.004) were higher in PSIS-CPHD than PSIS-IGHD.Conclusion: Later age at presentation and frequent hypogonadism were observed in our PSIS cohort. Male sex, sporadic presentation, clinical anomalies, and breech presentation predicted PSIS at presentation. Breech presentation in PSIS is likely due to stalk interruption rather than hormonal de ciency.

Clinical characteristics of a pediatric cohort of patients with combined pituitary insufficiency caused by mutations of the PROP1 gene

“…In the study group, we observed a signi cant male predominance in the CPHD-nonPROP1 group. This is consistent with observations of other authors describing similar cohorts (31).…”

Clinical Characteristics of Children with Combined Pituitary Hormone Deficiency and the Effects of Growth Hormone Treatment

“…Among our patients with GH deficiency, TSH was the most common accompanying deficit, followed by ACTH, FSH/LH, and ADH. Remarkably, similar to a previously reported cohort of 56 patients with PSIS 15 , none of our patients with PSIS had ADH deficit.…”

“…Similar to previous studies [14], the most prevalent cause of cCPHD in our cohort was PSIS. The high male-to-female ratio has been related to X-linked recessive genes and male susceptibility to prenatal and/or perinatal stresses [15]. The signs/complaints of short stature, followed by hypothyroidism, undescended testis/micropenis, hypoglycemia, delayed puberty, and polydipsia seen among our patients were also similar to previously reported commonly seen symptoms of prolonged jaundice, hypoglycemia, micropenis, or undescended testis in the newborn period and short stature or delayed puberty in childhood/adolescence [2,16].…”

“…In our cohort, additional defects were typically diagnosed in the peripubertal period. Increased demands for hormonal regulation during the peri-and postpubescent stages were associated with the development of multiple pituitary hormone deficiencies [15]. Patients in transition periods are particularly susceptible to hypopituitarism; hence, they should be carefully evaluated for the development of deficits.…”

Robo1 loss has pleiotropic effects on postnatal development and survival

“…These congenital disorders manifest as growth hormone deficiencies, lower body weights, and delayed growths in height, which is caused by pituitary dwarfism and the resulting deficiency in pituitary hormone release. While the underlying molecular mechanisms of these disorders remain unknown, it has been suggested that mutations in POU1F1, PROP1, and PTCH1 contribute to PSIS (Brauner et al, 2020;Diwaker et al, 2022). For the first time, our study provides functional evidence for the role of Robo1 deficiency as a cause for human disorders and presents a promising potential animal model.…”