CAJ | 학술논문

目的总结儿童期特发性低促性腺激素性性腺功能减退症(IHH)患者的临床特点及KAL1、FGFR1基因突变特点,探讨IHH诊断方法.方法分析2008年12月至2013年2月临床诊断为IHH的21例患儿的临床资料,包括人口学资料、主诉、现病史、家族史、体格检查、实验室检查及影像学检查等,并以50名健康儿童作基因研究的对照,研究检测KAL1、FGFR1基因的全部外显子及侧翼序列.结果 21例IHH患儿就诊年龄为8～17岁,平均(13.58 ±2.38)岁,男19例,女2例.其中Kallmann综合征(KS)患儿16例,占76％,余5例为嗅觉正常的IHH (nIHH).19例男性患儿中单纯青春期性不发育者2例,单纯小阴茎8例,单纯隐睾1例,隐睾伴小阴茎8例(其中1例KS患儿同时伴有尿道下裂).仅2例女性13岁和16岁患儿因青春期不发育来诊.其他临床表现:伴随男性乳房发育1例,智力低下2例,聋哑1例,高腭弓1例,双手联动1例,1例左肾缺如但肾功正常;基础黄体生成素、卵泡刺激素、睾酮均为青春期前水平.19例男性患儿中7例标准人绒毛膜促性腺激素(HCG)试验正常(睾酮＞1 100 ng/L),另有9例继续完成HCG延长试验,其中有2例(例6,8)睾酮值未升至1 000 ng/L以上.家族史:青春期延迟9例,其中父母之一6例,父母均迟2例.舅舅小阴茎1例,有正常后代;父亲嗅觉减退1例.11例IHH同时伴嗅觉异常且MRI可见嗅觉器官异常,4例MRI示嗅觉器官异常但嗅觉正常,1例嗅觉异常,但MRI未见嗅觉器官异常表现;15例(12例KS和3例nHH)行KAL1和FGFR1基因检测,发现例17 KAL1基因第7外显子c.1062+ 1G＞A剪接位点突变和例14 FGFR1基因第1外显子c.27delC移码突变,导致终止密码子提前出现.结论儿童期nIHH/KS诊断主要依靠临床表现,小阴茎或隐睾比例高,嗅觉和家族史是重要线索.嗅球部MRI为早期诊断KS的重要手段.KAL1基因及FGFR1基因突变率较低,非KS的主要病因.
목적 총결인동기특발성저촉성선격소성성선공능감퇴증(IHH)환자적림상특점급KAL1、FGFR1기인돌변특점,탐토IHH진단방법.방법 분석2008년12월지2013년2월림상진단위IHH적21례환인적림상자료,포괄인구학자료、주소、현병사、가족사、체격검사、실험실검사급영상학검사등,병이50명건강인동작기인연구적대조,연구검측KAL1、FGFR1기인적전부외현자급측익서렬.결과 21례IHH환인취진년령위8～17세,평균(13.58 ±2.38)세,남19례,녀2례.기중Kallmann종합정(KS)환인16례,점76％,여5례위후각정상적IHH (nIHH).19례남성환인중단순청춘기성불발육자2례,단순소음경8례,단순은고1례,은고반소음경8례(기중1례KS환인동시반유뇨도하렬).부2례녀성13세화16세환인인청춘기불발육래진.기타림상표현:반수남성유방발육1례,지력저하2례,롱아1례,고악궁1례,쌍수련동1례,1례좌신결여단신공정상;기출황체생성소、란포자격소、고동균위청춘기전수평.19례남성환인중7례표준인융모막촉성선격소(HCG)시험정상(고동＞1 100 ng/L),령유9례계속완성HCG연장시험,기중유2례(례6,8)고동치미승지1 000 ng/L이상.가족사:청춘기연지9례,기중부모지일6례,부모균지2례.구구소음경1례,유정상후대;부친후각감퇴1례.11례IHH동시반후각이상차MRI가견후각기관이상,4례MRI시후각기관이상단후각정상,1례후각이상,단MRI미견후각기관이상표현;15례(12례KS화3례nHH)행KAL1화FGFR1기인검측,발현례17 KAL1기인제7외현자c.1062+ 1G＞A전접위점돌변화례14 FGFR1기인제1외현자c.27delC이마돌변,도치종지밀마자제전출현.결론 인동기nIHH/KS진단주요의고림상표현,소음경혹은고비례고,후각화가족사시중요선색.후구부MRI위조기진단KS적중요수단.KAL1기인급FGFR1기인돌변솔교저,비KS적주요병인.
Objective To summarize the clinical features of idiopathic hypogonadotropic hypogonadism(IHH) diagnosed during childhood,and detect mutations in KAL1 and FGFR1,acting as key clues for diagnoses.Method We collected and analyzed clinical data of 21 cases (including demographic data,chief complaint,history of present illness,family history,physical examination,laboratory tests and imaging studies,etc.) diagnosed with IHH from December 2008 to February 2013.Polymerase chain reaction and gene sequencing was applied to detect mutations on KAL1 and FGFR1.Fifty healthy unrelated individuals were choosen as controls.Result Of 21 patients with IHH,19 were males and 2 females,they visited us initially from 8-17 years old,with an average of (13.58 ± 2.38)years old.Sixteen cases were KS patients(76％).One boy reported abnormal sense of smelling but having olfactory perfect picture on MRI;2/19 male cases had no puberty when they were over 13-14 years old without abnormal external genitalia.8/19 cases only had small penis,8/19 had both of cryptorchidism and small penis,and the Case 2 also had hypospadias.One boy had cryptorchidism combined with a normal penis.Only 2 girls diagnosed as IHH who visited us because of no puberty signs when they were 13 and 16 years old,respectively.Other clinical manifestations included:one with gynecomastia,2 had mental retardation,and one was deaf; one with high palatal arch; one with mirror-movement and one with left renal agenesis but normal renal function respectively.Laboratory tests showed that the basic testosterone (T) is low and with inappropriately low or normal gonadotropin hormones.The results of cases of standard human chorionic gonadotropin(HCG) test of 7cases out of 19 male children's were normal (testosterone ＞ 1 100 ng/L),and another nine cases continued to complete the extended HCG test,and the testosterone levels of two of them (cases 6,8) were still lower than 1 000 ng/L.Family history:the parents in 9/21 family had delayed puberty,involving only one parent in 6 families,involving both in 2 families and the other one was an uncle having micropenis with a child.Among these 21 cases,only one boy's father had hyposmia and his first emission age was 14-15 years.Eleven patients accompanied abnormal sense of smelling and the olfactory organ abnormalities on MRI,4 had olfactory organ abnormalities on MRI while they had good smelling function self-reportedly.We got 15 samples(12 KS and 3 nIHH cases)to screen the mutation of KAL1 (14 exons) and FGFR1 (18 exons).A splicing mutation c.1062 + 1G ＞ A in KAL1 is identified in case17 with IHH.One novel heterozygous FGFR1 mutation,a single base deletion mutation on the exon 1 c.27delC is identified in case 14.This mutation causes the premature termination codons.Conclusion This pilot research showed that IHH/KS diagnosis in children depends on clinical manifestation rather than gene analysis.Small penis or cryptorchidism,smelling abnormality and positive familial history may contribute to the KS/HH diagnosis.MRI of olfactory bulb acts as important proof for diagnosis of KS.Mutations in KAL1 and FGFR1 gene are not main causes of Kallmann syndrome.