In this large monocentric series of PSIS patients from Western India, the most common presentation was in childhood with short stature (64.3%), followed by delayed puberty (28.5%) in adolescence. Neonatal hypoglycemia, neonatal jaundice, hyperprolactinemia, and NVPS were significantly higher in PSIS-CPHD patients than in the PSIS-IGHD patients. Most PSIS patients had hypogonadism on evaluation at pubertal age (IGHD: 77%, CPHD: 91.3%), while new-onset cortisol (IGHD: 5%, CPHD: 33%) and thyroid (IGHD: 20%, CPHD: 0%) axis deficiencies were less common. Male predominance, sporadic presentation, CIAA, and EPMI were more frequent in the PSIS-IGHD patients than GHRHR-IGHD patients. Male predominance, sporadic presentation, BP, CIAA, and EPMI were more frequent in the PSIS-CPHD patients than those with POU1F1/PROP1-CPHD.
Median age at diagnosis of PSIS varied from 2.5 (range: 0-16.3) years in a French cohort to 25 (range: 22–28) years in a Chinese series (Table 2) [8, 9, 16–21]. The age at presentation was largely influenced by whether the report was published from pediatric or adult endocrine departments. Our endocrine unit caters to both pediatric and adult patients; hence, our cohort had patients presenting at varied ages (range: 0.3–37). In a PSIS cohort from Spain, though 30.8% were diagnosed in adulthood (≥ 18years), most had received growth hormone or sex steroids prior[22]. In our series, 23.2% (13/56) of patients received the first medical attention for hormonal deficiency in adulthood (≥ 18years), suggesting a delay in diagnosis and/or specialist referral probably due to resource constraint settings.
Table 2
Phenotypic data of pituitary stalk interruption syndrome with growth hormone deficiency cohorts (> 50 patients from single center).
Sr.no
|
Patients (n)
|
Age at diagnosis (years)
|
Multiple hormone deficiency (%)
|
Male: Female ratio
|
Breech
presentation (%)
|
Extra pituitary birth defect (%)
|
Familial cases (%)
|
Author's name, country, [reference]
|
1.
|
67
|
2.5 (range, 0-16.3)
|
48
|
1.7
|
19
|
48
|
0
|
Bar et al, France [16]
|
2.
|
60
|
4.8 ± 4.1
|
50
|
1.9
|
-
|
52
|
8.8
|
Simon et al, France [8]
|
3.
|
93
|
9.64 ± 5.04
|
> 92.5
|
3.7
|
46
|
-
|
-
|
Wang et al, China [18]
|
4.
|
62
|
11.5 ± 3.9 (range,4-21.6)
|
81
|
2.3
|
27
|
18
|
-
|
Melo et al, Brazil [9]
|
5.
|
59
|
12.5 (9.6–17.3)
|
100
|
5.6
|
91.5
|
-
|
-
|
Wang et al, China*[19]
|
6.
|
56
|
12.5 (6.25–16.75)
|
64.3
|
4.1
|
35.7
|
35.7
|
0
|
Current study, India
|
7.
|
53
|
Post pubertal age
|
54.7
|
1.2
|
21
|
46
|
-
|
Pham et al, France [20]
|
8.
|
55
|
19.7 ± 6.7
|
> 95.8
|
6.9
|
88.9
|
9.1
|
0
|
Guo et al, China [21]
|
9.
|
74
|
25 (22–28)
|
> 97.2
|
3.6
|
44.6
|
4
|
-
|
Wang et al, China [17]
|
*21 patient have history of receiving growth and sex hormone treatment. |
In this study, male sex, sporadic presentation, BP, CIAA, and EPMI predicted PSIS in both IGHD and CPHD groups. Several PSIS series have reported a higher male to female ratio (1.7 to 6.9) among PSIS patients (Table 2), which has been hypothesized to be due to a role of X-linked recessive genes, sex chromosome-environmental interactions, or an unexplained male susceptibility to prenatal insults [23].
Sporadic presentation as a predictor of PSIS in our series may be skewed due to comparison with the genetic cohorts. Nevertheless, several other series have reported a rarity (0-8.8%) of familial occurrence with PSIS (Table 2). Many pathogenic and candidate genes have been implicated but with a low yield (~ 5%) [1]. This re-affirms the minimal role of monogenic factors in the pathogenesis of PSIS. Another specific association with PSIS is extra pituitary birth defects, described in 4–52% of patients (Table 2). The presence of CIAA and EPMI can predict an early diagnosis of PSIS. Association with birth defects in PSIS could be explained by defects in early embryonic development, which may concurrently involve various organ systems.
The prevalence of BP [36%, IGHD: 20%, CPHD: 40%) was high in our PSIS cohort, which is consistent with most previous reports (19-91.5%) (Table 2). This is in contrast to IGHD/CPHD patients with established genetic diagnoses in whom the prevalence of BP is comparable to the general population [24]. Hence, a history of BP in IGHD/CPHD patients should raise clinical suspicion for PSIS. However, the pathophysiological link between BP and PSIS is unknown. The high prevalence of BP in PSIS cohorts but not in IGHD/CPHD patients with molecular diagnosis suggests a strong association of BP with stalk interruption rather than pituitary hormonal deficiency. We hypothesize that the lack of a yet-unknown factor from the fetal hypothalamic-pituitary axis that regulates fetal head engagement may be responsible for the frequent occurrence of BP in PSIS.
Perinatal events like neonatal hypoglycemia (22% vs. 0%) and jaundice (42 vs. 5%) were higher in the PSIS-CPHD cohort than the PSIS-IGHD but were comparable in PSIS-IGHD vs. GHRHR-IGHD and PSIS-CPHD vs. POU1F1/PROP1-CPHD. Thus, these perinatal events seem to be related to CPHD rather than PSIS per se. The majority (7/8) of patients with hypoglycemia had hypocortisolemia in our cohort. Glucose homeostasis in hypopituitarism, as in normal individuals, is primarily dependent upon the balance between insulin secretion and the secretion of hormones antagonistic to insulin, mainly cortisol [25]. Three of our PSIS infants presented with persistent hypoglycemia and/or cholestasis-related concerns had CPHD with both cortisol and thyroid deficiency. In a larger series of neonates with PSIS, hypoglycemia (15/16) and cholestasis (5/16) were common. Cholestasis was implicated due to cortisol deficiency with additive roles for GH or/and the TSH deficiencies[26]. Reduced immunohistochemical expression of bile canalicular transport proteins has been demonstrated in infants with cholestasis and CPHD [27]. Early diagnosis and appropriate hormonal replacements mitigate hypoglycemia and cholestasis in infants with CPHD.
In our cohort, PSIS-CPHD patients had a high prevalence of pubertal hypogonadism (91.3%) which is similar to most other PSIS-CPHD cohorts (80–100%) [2, 7, 22, 28, 29]. In contrast, progression to pubertal hypogonadism in patients with initial diagnosis of PSIS-IGHD is widely variable [(0% (0/6), 33% (2/6), 64% (7/11), and 77% (13/17)][2, 7, 22, 29]. Besides small sample size and comparison bias, variable severity of PSIS may contribute to this variability. Pubertal patients with IGHD with preserved gonadal axis may have a milder defect in hypothalamic-pituitary connection (trophic hormones) than those with IGHD progressing to hypogonadism. Following the continuum, patients with the most severe defect have multiple hormone deficiencies, including cortisol and thyroid axis. Our study showed that a higher proportion of PSIS-CPHD patients than PSIS-IGHD had absent stalk and hyperprolactinemia. Functional hyperprolactinemia (secondary to stalk interruption) may have an additive role in the pathogenesis of central hypogonadism. Prepubertal markers of hypogonadism (micropenis/cryptorchidism) were common [91% (10/11)] in PSIS children who developed hypogonadism in adolescence [2]. Similarly, in another French series of 53 postpubertal patients, micropenis was more common in PSIS-CPHD than PSIS-IGHD (69% vs. 13%)[20]. Hence, the history of micropenis/cryptorchidism in childhood is a clinical predictor of pubertal hypogonadism.
Many series have reported the occurrence of new-onset thyroid and cortisol deficiencies during follow-up, as also noted in three of our patients, of whom two had an initial diagnosis of IGHD. These observations suggest that either development of new-onset additional hormone deficiencies or the unmasking of a pre-existing gonadotropin deficiency is common overtime in PSIS-IGHD [30].
This is one of the largest series from the Indian subcontinent of PSIS and highlights late presentation and higher involvement of gonadal axis on follow up. Further, comparison with genetically diagnosed cases of IGHD/CPHD (eutopic posterior pituitary and normal stalk) provides additional insights into the association of perinatal events with PSIS or hormone deficiencies. However, our study is limited by retrospective study design and unavailability of genetics and gonadotropin stimulation tests in all patients.
To conclude, later age at presentation and higher evolution to hypogonadism were observed in our cohort. Male sex, sporadic presentation, associated CIAA and EPMI, and BP predicted PSIS at presentation as compared to genetic cohort. Breech presentation is likely due to stalk interruption rather than pituitary hormonal deficiency, in contrast neonatal hypoglycemia and jaundice are probably due to multiple hormone deficiency rather than structural defect per se. Further studies are warranted to understand the genetics of PSIS in Asian Indian patients.