The Assessment Of Etiolgy, Therapy And Prognosis For Children And Adolescents With Pituitary Stalk Interruption Syndrome

BackgroundPituitary stalk interruption syndrome (PSIS) is characterized by the presence of a thin or absent pituitary stalk, which is commonly associated with a hypoplastic or aplastic anterior pituitary or an ectopic posterior pituitary. This anatomical abnormality can be associated with other midline defects and variable endocrine disorders. Clinically, the syndrome is associated with either isolated GH deficiency (GHD) or multiple anterior pituitary hormone deficiency (MPHD). The causes of PSIS are still unknown. Some recent studies favor organogenesis defects that may be of genetic origin. Rare mutations of LHX4, HESX1, and more recently OTX2gene have been reported in PSIS. LHX4mutations have been reported to cause MPHD with variable neuroradiological abnormalities:PSIS, ectopic posterior lobe, pituitary hypoplasia, or defect of the corpus callosum and hindbrain. HESX1mutations have been reported in a broad spectrum of phonotypes such as septo-optic dysplasia (SOD).OTX2gene defects were recently reported in PSIS patients with or without ocular abnormalities. Recent studies indicated:perinatal insults were associated with thin/interrupted pituitary stalk, ectopic posterior lobe, and hypothalamic origin of hormonal deficiencies; in contrast, gene mutations were associated with consanguineous parents, intact pituitary stalk, and pituitary origin of hormonal deficiencies. In fact, more theories implicated traumatic birth, considering the high rate of perinatal events in this population. The patients had severe perinatal insults apparently leading to MPHD, such as breech delivery, transverse presentation, with or without asphyxia.Combined with test of endocrine hormone, magnetic resonance imaging (MRI) of hypothalamus-pituitary is particularly valuable for the diagnosis of PSIS. But there is an insidious development of hormone deficiencies leading to MPHD. Except for GHD, the other anterior pituitary deficiencies may occur at the time of diagnosis or while undergoing treatment. To date, there is still no effective method to predict severity and coexisting hormone deficiencies in PSIS patients. However, it is unknown whether morphological abnormalities can predict residual functions of pituitary in PSIS. Necessary hormone replacement therapy (HRT) has a definite therapeutic effect in PSIS. But controversies still exist in the timing and regimen of the HRT, especially, in the management of pituitary-gonadal deficiency.Therefore, a retrospective control analysis was performed to evaluate the etiology of PSIS, regimen of HRT, and prognostic factors.Objectives1. To assess the importance of different etiological factors for PSIS.2. To determine the role of different prognostic factors, such as the etiology, the pituitary morphological index, the initial treatment of age, and the regimen of HRT.MethodsPatients: Study Group:comprised72patients who fulfilled the criteria of PSIS diagnosed in Pediatric Department of Shandong Provincial Hospital from2010to2013.Control Group:enrolled60children and adolescents for health examination, who aged from4to24years. Of these,49were boys. There were no significant differences between the two arms for age or sex-ratio.1. To assess the importance of different etiological factors for PSIS.The clinical features of the72PSIS patients were collected by the use of a specific clinical report form. The data of the birth history were recorded in detail. We analyzed features of these PSIS patients and their parents and screened LHX4, HESX1and OTX2genes.2. To determine the effect of different etiological factors and pituitary morphological index on prognosis.2.1The patients were classified according to etiological factors. The index of pituitary morphology and the serum levels of pituitary-target hormones were measured in all of them. 2.2The patients were classified into two groups according to their MRI findings:Group I (partial PSIS), a very thin pituitary stalk with hypoplasia of anterior pituitary (HAP, defined as anterior pituitary height below the mean height of age-and sex-matched children), ectopic posterior pituitary (EPP) or absence of the posterior pituitary; Group II (complete PSIS), an interrupted or absent pituitary stalk (PSI) associated with the above situations. The serum levels of pituitary-target hormones before and after HRT, and the dosage of HRT were measured in all patients with PSIS.3. To study prognostic factors of PSIS patients who has reached final height (FH).The PSIS patient who has reached FH were selected and classified by height-SDS. The factors of etiology, pituitary morphology, and regimen of HRT were compared in order to find the main affecting factor.4. To evaluate the regimen of gonadotropin therapy for male patients with HH caused by PSIS.38PSIS patients coexisting with HH were selected and were divided into two experiment groups according to the initial ages of treatment or difference of pituitary stalk. Twenty two male14-24years old adolescents and young adults were enrolled in the control group for physical examination. In different experiment groups, all cases had undergone a pretreatment phase with hCG, which was administered to estimate the testicular functions and normalize the testosterone (TO) levels. After the pretreatment phase, the patients with normal serum TO concentrations were eligible to enter the phase of combined treatment with hCG and hMG, twice a week for6months. The serum levels of FT4, TSH, ACTH, COR, FSH, LH, TO, estradiol (E2), and prolactin (PRL) were measured in all experiment and control groups. And the testicular volume (TV) was tested every3months by the same observer.Results1. The importance of different etiological factors for PSISOf the72eligible patients,65were boys and7were girls (sex-ratio5.6:1).The neonatal data showed:breech delivery in59patients, head-presenting in11patients, and the other2had unknown delivery outcomes. Pituitary stalk interruption was far more common in babies with a history of a breech presentation (P＜0.001).There were2patients with other neuroradiological abnormalities:one with optic atrophy, and the other with absent septum pellucidum. Mutations of LHX4in5patients were found, and one of them wasn’t reported previously. But no disease-causing mutations of LHX4, HESX1and OTX2were observed in22patients and their parents.2. The effect of different etiological factors and pituitary morphological index on prognosisThere was no obvious relationship between pituitary morphology and gene mutations in the5patients with LHX4mutaions.72patients with PSIS were subdivided into two groups according to the appearance of the pituitary stalk:Group I (partial PSIS,34cases) and Group Ⅱ (complete PSIS,38cases). There was significantly small anterior pituitary in group II (P＜0.01). The incidence of ectopic posterior pituitary (EPP) was significantly higher in group Ⅱ (P＜0.01). In addition, there were significant differences in serum levels of growth hormone (GH), pituitary-thyroid hormones, and pituitary-adrenal hormones between two groups (P＜0.01).After HRT, there were no significant difference in the levels of pituitary-target hormones between PSIS patients and controls. The dosage of levothyroxine sodium in group Ⅱ was significantly higher than in group Ⅰ (P＜0.01), However, the dosage of hydrocortisol in group Ⅱ was slightly higher than in group Ⅰ, without statistical differences.3. The prognostic factors of PSIS patients who has reached final height (FH)There were17patients who reached the FH after HRT, and12patients have reached the standard of age-matched controls. In addition, there was positive correlation between Ht-SDS after rhGH (FH-SDS) therapy and course of treatment (p＜0.05), and negative correlation between ages of initiate treatment and FH-SDS (p＜0.05). Similarly, there was negative correlation between numbers of pituitary hormone deficiency and FH-SDS. No relation was found among appearance of pituitary stalk, dosage of rhGH, and benefit of height. 4. The regimen of gonadotropin therapy for male patients with HH caused by PSISThe levels of pituitary-gonadal hormones were no significantly different in different types of pituitary stalk, except testosterone (TO, P＜0.05). According to ages, these HH patients were subdivided into two experiment groups:Group Ⅰ (adolescents,14-18years old,25cases), and Group Ⅱ (young adults,18-24years old,13cases). Before gonadotropin therapy, there were no significant increases of gonadal hormones in two experiment groups. After treatment with the human chorionic gonadotropin (HCG) for less than3months, the hormone levels of pituitary-gonadal were significantly more increased in group Ⅰ than group Ⅱ, which showed a slow rise in elder patients. After adding the human menopause gonadotropin (HMG) for6months, the gonadal hormone levels of group Ⅱ were significantly increased. In addition, the tanner phase and penis lengths in group Ⅰ were significantly improved. There was no significant adverse impact on BMI and height velocity (HV) after less than one year therapy.Conclusions 1. On the basis of birth history, breech presentation may a forewarning for subsequent pituitary hormone deficiencies.2. MRI of pituitary can predict occurrence and severity of PSIS, which are also correlated with the levels of the pituitary-target hormone deficiencies. Interruption of pituitary stalk and ectopic posterior pituitary both represent important markers of pituitary structure and function.3. Long period without treatment may be responsible for growth and development, especially for HH patients caused by PSIS. Early supplementary therapy of hCG and hMG is beneficial for the recovery of gonadal hormone and development of secondary sexual characters.