Pituitary stalk interruption syndrome: a case report and review of the literature
Article Category: Clinical report
Online veröffentlicht: 31. Jan. 2017
Seitenbereich: 237 - 243
DOI: https://doi.org/10.5372/1905-7415.0902.393
Schlüsselwörter
© 2017 Yan Zhang, Changbin Quan, Weimin Li, Liying Chen, Xiaoyan Song, Jianbin Xu, Guangqing Zhu
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
Pituitary stalk interruption syndrome (PSIS) is usually characterized by a very thin or interrupted pituitary stalk, complicated by an ectopic posterior pituitary and impaired delivery of hormones secreted by the hypothalamus to the pituitary through the pituitary stalk, which results in dysplasia of the anterior pituitary [1]. PSIS was first described by Fujisawa in 1987 [2]. Chinese researchers used magnetic resonance imaging (MRI) and computed tomography (CT) of the sellar region in studies of primordial dwarfism as early as 1993 [3]. Since Ying Liu et al. first reported PSIS in China in 2004, a growing number of reports have been published, which mainly focus on imaging results of individual cases instead of clinical changes and laboratory test results. Here, we report a case of PSIS with obesity, and review the relevant literature.
A 36-year-old male patient required gastric banding surgery because of weight gain for 14 years. The patient was heavier than average as a child, which did not attract any attention. The patient was diagnosed with small pituitary at 8 years of age because he was shorter than his peers and had learning difficulties. Growth hormone was administered to the patient twice, but no improvement was observed. At age 21, the patient was 154 cm tall and weighed 68 kg. The patient was diagnosed with dysplasia of the reproductive organs at 22. He had not undergone puberty, as evidenced by his lack of pubic hair, armpit hair, Adam’s apple, voice cracking, and nocturnal erections and emissions, the latter indicating immaturity of the penis and testicles. Blood tests showed deficiency in thyroid-stimulating hormone (TSH), growth hormone (GH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), indicating anterior pituitary hypothyroidism. MRI showed a pituitary with small volume. Bone-age films showed that the patient had the bone age of a 16-year-old, but he refused testosterone undecanoate therapy at this time. At the most recent examination, his body weight had increased to 118 kg (height, 160 cm). The patient had no somnolence, dysosmia, polydipsia, diuresis, headache, dizziness, or visual field defect, and was eligible for gastric banding surgery. He had normal intelligence and was in good mental and physical condition. The patient had dyslipidemia for more than ten years without history of high blood pressure, diabetes, or coronary heart disease. He was single and had no children. His parents were not in a consanguineous marriage, and his brother and two sisters were healthy. The patient was his mother’s fourth delivery. He weighed 4 kg at birth and was delivered vaginally, but he suffered oxygen deprivation at birth because of dystocia.
Physical examination results were as follows: height, 160 cm (upper body, 84 cm; lower body, 76 cm); arm span, 160 cm; waist, 127 cm; hip circumference, 134 cm; weight, 118 kg; BMI, 47.3 kg/m2; no facial hair or Adam’s apple; developed bilateral breast; sparse pubic hair; penis length, 3 cm; and testicles could not be palpated.
Laboratory test results were as follows: testosterone, 0.87 (normal range 1.53–7.40) nmol/L; FSH, 0.27 mIU/mL (1.5–12.4); estradiol, 77.18 pmol/ L (40.6–288); LH, 1.41 IU/L (1.7–8.6); prolactin, 83.07 μg/L (2.1–17.7); GH <0.05 μg/L (0.06–5.0); insulin-like growth factor-1, 55.8 U; free thyroxine, 7.60 pmol/L (10.42–24.32); TSH, 2.23 mU (1.35–5.50); total thyroxine, 19.9 nmol/L (55.34–160.88); 8.00 AM adrenocorticotropic hormone (ACTH), 5.04 pmol/L [<10.12 (DPC)]; 12.00 PM ACTH, 3.57 pmol/L; 8 AM cortisol, 131.91 nmol/L (198.7–797.5); 12 PM cortisol, 75.02l nmol/L (0–165.7); insulin 0 h, 15.47 mU/L; insulin 2 h, 288.2 mU/L; C peptide 0 h, 3.16 ng/mL; C peptide 2 h, 17.48 ng/L; fibrinogen β chain 0 h, 4.20 mmol/L; PGB 2 h, 7.68 mmol/L; cholesterol, 5.75 mmol/L; triglyceride, 3.00 mmol/L; high density lipoprotein-cholesterol, 1.06 mmol/L; low density lipoprotein-cholesterol, 3.83 mmol/L; glutamate pyruvate transaminase, 56 IU/L; and glutamic oxaloacetic transaminase, 39 IU/L. Other blood and urine test results were normal. The electrocardiogram revealed a sinus rhythm and abnormal T wave. Gonadotropin releasing hormone stimulation test results were as follows: serum LH level was 0.17, 0.17, 0.69, 0.66, 0.64 IU/L 15 min before stimulation and at 0, 30, 60, 120 min, respectively. Serum FSH level was 0.76, 0.51, 1.19, 1.18, 1.63 IU/L 15 min before stimulation and at 0, 30, 60, 120 min, respectively. B ultrasound showed fatty liver disease, but biliary tree, pancreas, spleen, and both kidneys were normal. Right and left testes were 0.98 cm × 1.3 cm × 1.9 cm and 1.1 cm × 1.3 cm × 1.7 cm, respectively, and bilateral testicular volume was reduced with microcalcification. Left adrenal gland showed slight localized thickening without obvious abnormal density on imaging. The pituitary stalk was not evident by MRI scan.
Specialists outside of our hospital diagnosed the patient with PSIS, anterior pituitary hypofunction, and dyslipidemia. The patient was prescribed 5 mg of prednisone acetate in tablet form, which he took at 6 AM every day. One month later, the patient began receiving 50 μg of levothyroxine sodium every day, and 259 mg of testosterone undecanoate was injected intramuscularly 3 times per week. The patient made regular visits to an outpatient clinic to monitor his thyroid function, cortisol rhythm, gonadal hormones, blood fat, liver function, and to take other medical tests.
The search terms “pituitary stalk interruption syndrome,” “PSIS”, and “vertebral handle interrupts syndrome” were used to search the China Hospital Knowledge Database and Wanfang Database, and the results were limited to clinical research published between January 1, 2004 and December 31, 2013. This search returned 40 articles, but 7 of them were from a study of the same population, so we merged the data. In total, 33 articles were identified for further review (
Chinese database search resultsNo First author Published time Research location Time of data Methods No. of cases 1 Liu et al. [10] 2004/06 Shandong 2003 Case report 1 2 Zhao et al. [11] 2005/06 Nanjing 2003 Case report 1 3 Fang et al. [12] 2007/01 Guangdong 2007 MRI diagnosis 3 4 Tian et al. [13] 2007/09 Shandong 2003–2006 MRI diagnosis 10 5 Cheng et al. [14] 2008/06 Beijing 2005–2007 MRI and clinic 14 6 Li et al. [15] 2008/11 Guangzhou 2007 MRI diagnosis 4 7 Zheng et al. [16] 2009/03 Beijing 2007 Case report 1 8 Tu et al. [17] 2009/06 Anhui 2006–2008 MRI diagnosis 9 9 Xie et al. [18] 2009/10 Jiangxi 2005–2007 MRI and clinic 15/38 10 Rong et al. [19] 2010/06 Hebei 2010 Case report 1 11 Sang et al. [20] 2010/06 Henan 2009 Clinical analysis 8 12 Ren et al. [21] 2010/07 Ningbo, Zhejiang 2009 MRI diagnosis 3 13 Zheng et al. [22] 2010/10 Shandong 2009 Case report 1 14 Quan et al. [23] 2010/09 Hainan 2008 Case report 1 15 Lu et al. [24] 2010/12 Jiangsu 2009 Case report 1 16 Lai et al. [25] 2011/02 Liaoning 2010 Case report 1 17 Pan et al. [26] 2011/02 Beijing 2001–2010 MRI diagnosis 31 18 Lu et al. [27] 2011/02 Guangdong Unknown MRI diagnosis 14 19 Zheng et al. [28] 2011/04 Hangzhou, Zhejiang 2009 Nursing care 1 20 Liu et al. [29] 2011/05 Beijing 2005–2010 MRI diagnosis 18 21 Dong et al. [30] 2011/02 Tianjin 2010 Case report 1 22 Zheng et al. [31] 2011/11 Anhui Unknown Case report 1 23 Shu et al. [32] 2012/06 Nanchang, Jiangxi 2002–2009 Clinical study 53 24 Wu et al. [33] 2012/01 Zhengzhou, Henan Unknown Case report 1 25 Zhang et al. [34] 2012/02 Guangdong Unknown Case report 1 26 Chen et al. [35] 2012/02 Beijing 1997–2011 Clinical study 36 27 Wan et al. [36] 2012-4 Xiehe, Beijing 2010/7–2011/3 Clinical analysis 3/1 28 Cao et al. [37] 2012 Guangzhou Military Hospital 2011/8 Case report 1 29 Wang et al. [38] 2012 Hubei 2005/11–2007/3 MRI and clinic 13/1 30 Li et al. [39] 2013/01 Pingdingshan, Henan 2003–2012 MRI diagnosis 8/1 31 Liang et al. [40] 2010/10 Guangdong Unknown Clinical study 5/2 32 Wang et al. [41] 2010/04 Hangzhou, Zhejiang 2008/1–2009/6 Clinical analysis 9/4 33 Ye et al. [42] 2008/05 Fudan, Shanghai 2005–2007 Clinical diagnosis 4/1
A total of 311 cases of PSIS have been reported, comprising 257 male and 54 female patients. The age at diagnosis ranged from 40 days to 52 years, which was exactly the same as misdiagnosis time. Of the 311 cases, two cases were in infants (40- and 76-days-old) who presented with hypoglycemia and adrenal crisis. Of the cases in adults, two were unusual in that they showed normal growth and development. One 52-year-old patient was characterized by intolerance of cold, reduced sexual function, and normal growth and development; one female patient had diabetes insipidus, typical signs of PSIS on MRI, but normal growth and development, and no pituitary dysfunction. She was diagnosed with central diabetes insipidus. The remaining 307 patients were diagnosed at between 5 and 30 years of age, and they were characterized by growth retardation, missing secondary sex characteristics, and delayed bone age for more than two years. There were 12 cases of diabetes insipidus and one case of obesity.
Among 311 patients, one infant showed ambiguous border between the ectocinerea and the alba, low density signal and cerebral edema in the CT scan of the head, and was diagnosed with PSIS. All the other patients were diagnosed through cerebral MRI, and comprised 239 patients without pituitary stalk, 62 patients with thin pituitary stalk, 215 patients with ectopic posterior pituitary in the optic chiasm and infundibular recess, 34 patients without posterior pituitary, 5 patients without anterior pituitary, and 174 patients with thinning pituitary. Complications included agenesis of corpus callosum (2 cases), right hippocampus smaller than left (1 case), vacuole turcica (7 cases), cerebellar tonsillar hernia into the foramen magnum (2 cases), and hypophysoma (1 case).
Results of pituitary function tests were reported for 265 patients, of which 193 (72.8%) displayed lack of multiple pituitary hormones (GH, gonadotropin, TSH, ACTH, etc.). The other 70 patients (26.4%) were deficient in a single growth hormone. Secondary sex characteristics were missing in one patient in which GH level was normal. One patient had diabetes insipidus.
Of 311 patients, 265 exhibited a relationship between pituitary abnormalities and hormone deficiency. Pituitary stalk interruption was evident in 217 patients (81.9%), including 185 (85.3%) with deficiency of multiple pituitary hormones, and 31 patients (14.3%) with deficiency of a single growth hormone. Image examination showed pituitary stalk thinning in 48 patients (18.1%), of whom 8 exhibited a deficiency in multiple pituitary hormones and 39 patients were deficient in a single growth hormone. χ2 was 85.69 (
Among 265 patients, the anterior pituitary was small, thin, or absent in 207, of which 80.7% resulted from pituitary stalk interruption and 19.3% were caused by pituitary stalk thinning. Among 259 patients with posterior pituitary ectopia or absence, 93.4% were because of pituitary stalk interruption and 6.6% were because of pituitary stalk thinning.
Among 311 patients, 155 (49.8%) had an explicit history of abnormal parturition, 67 (31.5%) had a history of cerebral anoxia, 48 patients’ (22.5%) mothers had experienced pregnancy abnormalities while the patient was in utero, 45 patients (21.6%) were born in a bad parturition environment, and 5 patients had cerebral trauma (1.6%).
Only 12 patients (3.86%) out of 311 patients with PSIS accepted growth hormone therapy. After treatment, 8 of them increased body height 1.4–11 cm, including 3 patients who were between 17 and 20 years old at the time of the treatment. Four patients ended therapy early for financial reasons.
Since 2004, China has reported a total of 311 patients with PSIS in 33 articles, making PSIS a rare disease with a prevalence of 1/1000–1/10000 [4]. The actual prevalence of PSIS might be underestimated because of the limitations of our understanding of the disease and our methods of diagnosis. Although this disease does not affect survival, it influences the quality of life for the patients and their families. Consequently, it deserves attention from pediatricians, obstetricians, and endocrinologists. Of the 33 articles, 14 described single patients and 3 reported 2–4 cases; only a few reports summarized and analyzed a larger population of patients. Of these, 10 focused on MRI changes. Here, we report cases of adult patients who were diagnosed after puberty. Only 12 patients accepted therapy, and of those, 8 improved their body height, which indicated that even adult patients could benefit from treatment. Earlier diagnosis and treatment could help more patients improve their life condition.
Problems during pregnancy and birth were common. Two-thirds of the 311 patients were born after abnormal pregnancies or parturition, or they had experienced cerebral anoxia inside or outside the uterus. All this strongly suggests that difficulties during childbirth (e.g., breech birth, cesarean section) are a main cause of pituitary stalk interruption. Sheelan and Whitehead discovered that the pituitary was easily fractured [5] during autopsy, and most scholars consider abnormal parturition the main risk factor for PSIS [3, 6]. Therefore, PSIS could be prevented by protecting infants during the perinatal period. In addition, close monitoring of the growth and development of those children who experienced abnormal parturition, including performing MRI to determine whether the pituitary stalk was injured in patients with suspected PSIS, and employing suitable therapy as early as possible, could avoid or reduce disability.
Because of the large population of China, the number of people with dwarfism is relatively high (180 articles reported 7226 cases of nanism between 2010 and 2012). Laboratory screening of hormone levels is quite common, but researchers often do not realize the importance of pituitary imaging. Japanese researchers [2] reported PSIS in 1980s, but Chinese doctors could not diagnose this disease until 2004 [7] because of the limitations of our imaging equipment. Our review demonstrates that PSIS is not as rare as was thought. In the case we reported, no conclusion could be drawn from the first 2 cerebral MRI and CT scans. The patient was diagnosed with PSIS only after a third MRI scan, which was read by an expert who was called for consultation. This strongly indicates the necessity of a better understanding of this disease by endocrinologists and pediatricians. The sellar region should be closely examined by MRI in patients with multiple pituitary hormone deficiency or single growth hormone deficiency, especially those with a history of abnormal pregnancy and parturition, cerebral anoxia, or both. Our study revealed that the type of damage to the pituitary stalk closely correlates with the hormone deficiency type; for example, patients without pituitary stalks were deficient in multiple pituitary hormones and patients with thin pituitary stalks were deficient in a single growth hormone. The difference between the two groups was significant, a finding that was consistent with what Komreich et al. [8] has reported. In this case, it seems that missing and thinning pituitary stalk are different damage levels. It is also possible that these abnormalities reflect gene deficiencies, and such a possibility deserves further investigation. If the incidence of PSIS could be reduced by protecting infants during the perinatal period, this disease might be renamed as pituitary stalk injury syndrome, which could attract more attention.
Because the pituitary stalk is the only route of blood circulation and the only channel of contact between the hypothalamus and the pituitary, all the patients with PSIS are characterized by anterior pituitary dysplasia. This is because pituitary stalk damage prevents hypothalamus-secreted growth hormone releasing hormone, gonadotropin releasing hormone, thyrotropin releasing hormone, and corticotropin releasing hormone from passing from the pituitary stalk through the supraopticohypophyseal tract to be delivered to the anterior pituitary. The lack of these hormones results in abnormal hormone secretion by the anterior pituitary. In our review, most PSIS patients with anterior pituitary abnormalities had a small, thin, or absent anterior pituitary, and shared clinical features of multiple pituitary hormone deficiency. These observations are consistent with reports in the literature that multiple pituitary hormone deficiency is more common than single growth hormone deficiency [9]. There were 256 cases of abnormal or absent posterior pituitary, but only 12 cases of diabetes insipidus. Some researchers have suggested that pituitary stalk damage interrupts the drainage of vasopressin and antidiuretic hormone from the hypothalamus to the posterior pituitary, but the reason for the low incidence of diabetes insipidus is collateral flow between the hypothalamus and the pituitary [4]. Therefore, although MRI scan did not show a pituitary stalk, the ectopic posterior pituitary was similar to normal; high signal was exhibited on T1-weighted imaging and the minority exhibited normal signal because of antidiuretic hormone particles, which further indicated that the function of the posterior pituitary was normal.
In conclusion, most patients were male, diagnosed late, and inadequately treated. MRI mainly showed missing pituitary stalk and posterior pituitary ectopia, followed by pituitary stalk thinning, and anterior pituitary thinning and absence. MRI scans and a pituitary hormone test are important methods for diagnosis of this disease. For infants who experienced anomalies during pregnancy and perinatally complicated with growth retardation, MRI scans and pituitary hormone tests could facilitate early diagnosis and treatment, and improve prognosis. To control PSIS in the future, we recommend more research into protecting infants from complications during pregnancy and parturition, and closely monitoring those who do suffer these complications for early signs of PSIS.
All of the authors declare that they have no conflicts of interest regarding this article.