Clinical Feature And Gene Analysis Of Pituitary Stalk Interruption Syndrome

Objective1. To analyze the clinical characteristics of 114 cases with pituitary stalk interruption syndrome(PSIS).2. To analyze the impact of the deficiency of pituitary stalk (disrupted or thin pituitary stalk) on the clinical signs and hormone level.3. To explore the relationship between the gene PROKR2、PROK2、ESX1、LHX3、 LHX4、OTX2、SOX3、PROP1、POU1F1 mutations and PSIS patients.4. To investigate the difference in the frequency of PROKR2、HESX1、LHX3、 LHX4、OTX2、SOX3 and PROP1 genetic changes between PSIS patients and normal individuals.Methods1.114 patients with PSIS in our hospital were retrospectively analyzed, regarding clinical manifestation, laboratory and imaging data.2. The clinical signs and hormone levels from two groups of PSIS patients with deficient pituitary stalks (disrupted or thin pituitary stalk) were investigated to gain a better understanding of PSIS. In total,89 male patients were divided into two groups according to the degree of deficiencys of the pituitary stalk:thin pituitary stalks (group 1, n=17) and disrupted pituitary stalks (group 2, n=72).3. PROKR2、PROK2、HESX1、LHX3、LHX4、OTX2、SOX3、PROP1、POU1F1 genotypes were identified by multiplex polymerase chain reaction analysis with exon-flanking primers and by automated sequencing techniques with peripheral blood DNA samples from 59 patients with PSIS.4. On the basis of the sequences of above genes and genetic change sites that were detected in the third part of the experiment,100 healthy controls of the same ethnicity were included, sequencing was performed for genetic changes sites, and genetic change rates were compared between PSIS patient group and control group.Results1. Of the 114 patients with PSIS,102 cases (89.4%) were male. The average age was 21.1±6.1 years. A history of breech delivery was documented in 91 cases (91.9%). Short stature was found in 89 cases (71.8%) and bone age delayed 6.13±5.14 years. Secondary sex characteristics were poor or undeveloped in most patients. The prevalence of deficiencies in growth hormone, gonadotropins, corticotropin, and thyrotropin were 100%,94%,84.2%,74.6%, respectively. Hyperprolactinemia was found in 28.1% of patients. Three or more pituitary hormone abnomal were found in 92.1% of the patients. Compared with the 5 cases with history of cephalic delivery, no difference were found in the aspects of height, penile lengths, testicular volume, the height of anterior pituitary in the 53 cases with history of breech delivery. All patients had normal posterior pituitary function and absent or thin pituitary stalk on imaging. The average height of anterior pituitary was 2.9±0.8 mm, documented anterior pituitary hypoplasia.2. The clinical manifestations were assessed and compared to Group 2, the patients in Group 1 demonstrated significantly higher height, penis length, testicle volume and pituitary height(P<0.05). There were no significant differences in the rate of breech presenting or the incidence of associated congenital malformations/diseases between Group 1 and Group 2. Upon examing the hormone levels, the following hormone secretion peaks were greater in Group 1 than that in Group 2:growth hormone (GH), adrenocorticotropic hormone (ACTH) and luteinizing hormone (LH) (P<0.05). In contrast, there was no difference in the thyroid-stimulating hormone (TSH) between Group 1 and Group 2.3.6 PSIS patients showed single nucleotide polymorphism at the PROKR2 locus. Of them,5 patients exhibited intragenic substitution of exon 2 (c.991G>A), and the another patient exhibited intragenic substitution of exon 2 (c.1057C>T).1 PSIS patient showed single nucleotide polymorphism at the HESX1 locus. The patient exhibited intragenic subsititution of exon 1 (c.142A>T).1 PSIS patient showed single nucleotide polymorphism at the LHX3 locus. The patient exhibited intragenic subsititution of exon 2 (c.806C>T).62 PSIS patients showed single nucleotide polymorphism at the LHX4 locus. Of them,10 patients exhibited intragenic subsititution of exon 1 (c.63T>C),1 patient exhibited intragenic subsititution of exon 3 (c.450C>T), and 51 patients exhibited intragenic subsititution of exon 6 (c.983A>G).1 PSIS patient showed single nucleotide polymorphism at the OTX2 locus. The patient exhibited intragenic subsititution of exon 1 (c.1123T>C).6 PSIS patients showed single nucleotide polymorphism at the SOX3 locus. Of them,4 patients exhibited intragenic subsititution of exon 1 (c.157G>A), and 2 patients exhibited intragenic subsititution of exon 1 (c.1131 G>A).56 PSIS patients showed single nucleotide polymorphism at the PROP1 locus. Of them,46 patients exhibited intragenic subsititution of exon 1 (c.27T>C), and 10 patients exhibited intragenic subsititution of exon 3 (c.424G>A). No single nucleotide polymorphism were found in the PROK2 and POUIF1 on PSIS patients.4. No statistical significance was found in the frequency of PROKR2、HESX1、 LHX3、LHX4、OTX2、SOX3 and PROP1 genetic change rates between PSIS patient group and control group(P>0.05). Conclusions1. The clinical features of PSIS patients seem to be different from other reported patients in regarding to the higher degree of hypopituitarism. The severity of patients condition was no difference in cases with history of the two delivery ways.2. Our data suggest that PSIS patients with a disrupted pituitary stalks present worse clinical manifestations, more sever pituitary hypoplasia and lower hormone levels compared with PSIS patients that had a thin pituitary stalk.3. It’s not definitive yet that PROKR2、HESX1、LHX3、LHX4、OTX2、SOX3、 PROP1 mutations are a causative factors for PSIS. No association between PROK2, POUIF1 and PSIS was found in the study. Further studies are needed.4. No statistical significance was found in the frequency of PROKR2、HESX1、 LHX3、LHX4、OTX2、SOX3 and PROP1 genetic change rates between PSIS patient group and control group.