| Part I Genetics Mutation Analysis of Congenital Pituitary DysplasiaIntroductionCongenital pituitary dysplasia has one or more pituitary hormone deficiencies and its most common clinical manifestation is growth delay and absence of puberty or incomplete puberty.It belongs to the midline diseases and some patients have an association of an absent or thin pituitary stalk,pituitary hypoplasia,and/or ectopic neurohypophysis on pituitary MRI,also named as pituitary stalk interruption syndrome.It was thought perinatal complication was associated with the disease previously.However,as more and more associated genes were reported in patients with congenital pituitary dysplasia,now genetic mutation analysis has become the hot focus of its mechanism.To date,30 genes have been reported to be involved in the pathogenesis of congenital pituitary dysplasia.GLI2,HESX1,LHX-3,LHX4,OTX2,POUIF1,PROP1 and SOX2 are the most studied ones.However,most studies only analyzed 1 to 5 gene mutations and some genes are only reported in one case.Consequently,next generation sequencing is needed to analysis all the reported gene mutation in a large population.Besides,few studies on congenital pituitary dysplasia in China were reported.Objective1.To summarize clinical characteristics of patients with congenital pituitary dysplasia.2.To screen the potential pathogenic genes of congenital pituitary dysplasia.Subjects and Methods1.Subjects:86 patients with congenital pituitary dysplasia admitted to Endocrinology department of Peking Union Medical College Hospital between 2013.1 and 2016.11 were included.2.Methods:(1)Clinical study:clinical characteristics of congenital pituitary dysplasia were summarized.(2)Genetic mutation analysis:next-generation sequencing including 85 candidate genes associated with congenital pituitary dysplasia was used to identify rare gene mutations in patients with congenital pituitary dysplasia.Candidate gene mutations were compared with known genetic database.Computer software of SIFT,Polypen-2 and Mutation taster were used to predict protein function.Results1.In this study,two patients come from the same pedigree,and others are sporadic cases.88.4%of patients have perinatal complications.Except that cryptorchidism was reported in 4 patients,short neck in one patient,ongenital deafness and ichthyosis in one patient,others have no midline deformities.2.GH deficiency was present in 100%of cases,gonadotropin deficiency in 97.7%,TSH deficiency in 80.2%,ACTH deficiency in 48.8%and diabetes insipidus in 5.8%.3.MRI revealed that 98.8%had pituitary stalk interruption syndrome,of which two patients also have extra-pituitary abnormalities,with one having Dyke-Davidoff-Masson syndrome and the other having corpus callosum dysplasia.Besides,one patient has only anterior pituitary dysplasia.4.Rare gene mutations of 26 candidate genes were revealed in 41.9%of patients.All these rare mutation were novel mutations.One is nonsense mutation and the others were missense mutations.Sanger sequencing proved all the rare mutations detected by next-generation sequencing were correct.5.16.3%of patients have rare gene mutation of the 19 associated genes with the congenital pituitary dysplasia reported previously,but family segregation and in vitro experiment were still needed to assign causality.Conclusion1.Patients with congenital pituitary dysplasia in China are almost all sporadic and they have high frequency of perinatal complications.Growth hormone and gonadotropin are most common pituitary hormone deficiencies.Besides,most patients have pituitary stalk interruption syndrome on pituitary MRI.2.This study showed that the gene mutation frequency of reported genes associated with congenital pituitary dysplasia in Chinese patients is low.IntroductionCongenital combined pituitary hormone deficiency(CCPHD)has at least two kinds of anterior pituitary hormone deficiency and its most common clinical manifestation is short stature and absence of puberty or incomplete puberty development.CCPHD is a developmental defect and some patients with CCPHD also show pituitary stalk interruption syndrome(PSIS)which is characterized by a triad of morphological anomalies that can be visualized by pituitary magnetic resonance imaging(MRI),including an absent or thin pituitary stalk,pituitary hypoplasia,and/or ectopic neurohypophysis.Given the underlying pituitary abnormalities,it should come as no surprise that CCPHD patients often present with multiple pituitary hormone deficiencies.Gonadotropin deficiency occurs in approximately 76.9%-100%of CCPHD patients.The effectiveness of pulsatile gonadotropin-releasing hormone(GnRH)therapy in patients with CCPHD has not been investigated due to the limited number of patients as well as these patients' presumed pituitary hypoplasia,poor gonadotrophic cell reserve,and impaired gonadotrophic response to GnRH.ObjectiveTo assess the pituitary response to pulsatile GnRH therapy in men with CCPHDSubjects and MethodsSubjects40 male patients with CCPHD were recruited from an existing CCPHD population in Peking Union Medical College Hospital between November 2015 and June 2016.Patients were selected based on the following criteria:(1)Absent or incomplete pubertal development by 18 years of age;(2)Multiple(at least 2)anterior pituitary hormone deficiencies,including gonadotropin deficiencies;(3)Sellar MRI showing(a)an absent,thin or interrupted pituitary stalk,(b)pituitary hypoplasia,and/or(c)ectopic posterior pituitary.MethodsA prospective and self-controlled clinical trial was conducted.Interventions and Outcome measurementsPulsatile GnRH was administered subcutaneously via a portable infusion pump for three months.In each patient,the GnRH dose was initiated at 10 ?g/90min and was progressively adjusted to maintain serum testosterone levels between 6.94-17.35 nmol/L(200-500 ng/dL).The maximum GnRH dose was set at 15 ?g/90 min.Subjects were evaluated at one and three months.At each follow-up visit,the outcome measurements included serum total serum testosterone,LH and FSH levels,testicular volumes and semen analysis.Results1.A total of 40 male CCPHD patients completed the study.At first assessment,both GH and gonadotropin deficiencies were present in 100%of cases,TSH deficiency in 85%,ACTH deficiency in 50%,and diabetes insipidus in 5%.2.All patients had perinatal complications,including breech delivery in 38 cases,cesarean section due to prolonged labor duration in one case,and premature delivery in one case.In addition,neonatal asphyxia was reported in 8 cases and intracranial hemorrhage in three cases.3.Of these,60%(24/40)showed a good response to pulsatile GnRH treatment(response group),and their LH and FSH levels increased into the normal range and testosterone levels also increased to 8.67±4.83 nmol/L at three months.Of the patients in the response group,33.3%(8/24)of them achieved spermatogenesis and the mean sperm concentration was 5.51±3.36 million per mL at three months.4.The remaining 40%(16/40)of patients had a poor response to pulsatile GnRH treatment.After three months,this group showed an increase in LH levels from 0.19±0.29 IU/L to 1.09±0.77 IU/L(p=0.002)and FSH levels increased from 0.53±0.50 IU/L to 3.19±1.75 IU/L(p=0.001).Although serum testosterone levels remained unchanged and as low as 0 nmol/L after pulsatile GnRH treatment,testicular volume increased slightly from 1.9±0.7mL to 2.9±2.0mL(p=0.018).5.MRI did not reveal any correlation between pituitary response and pituitary height and/or integrity of the pituitary stalk.6.Serum LH levels above 3 IU/L at one month seemed to suggest a good response to continued pulsatile GnRH therapy,LH levels below 2 IU/L at one month seemed to suggest a poor response,but those with LH levels between 2 IU/L and 3 IU/L will require longer follow-up times before any definitive conclusions can be made.Conclusion1.Pulsatile GnRH therapy restored pituitary-testis axis function in 60%of patients with CCPHD.2.This study suggests that gonadotrophs in CCPHD patients can exist and be functional—even with MRI evidence of pituitary hypoplasia or dysplasia.3.These results may directly guide the clinical therapeutic choice. |
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