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Children with Idiopathic Hypogonadotropic Hypogonadism: Clinical Data Analysis and Mutations Analysis of KAL1and FGFR1Gene

Author: QinZuo
Tutor: GongChunXiu
School: Capital University of Medical Sciences
Course: Pediatrics
Keywords: Kallmann syndrome hypogonadotropic hypogonadism gonadotropin-releasing hormone diagnosis treatment
CLC: R725.8
Type: Master's thesis
Year: 2013
Downloads: 18
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Abstract

Objective1. To study the clinical features and diagnostic methods of idiopathichypogonadotropic hypogonadism(IHH) during childhood, and study the possibility oftreatment at early stages so as to lay a foundation for observation on effectiveness ofearly interventions.2. To detect mutations in KAL1and FGFR1, acting as key clues for diagnoses,mutation analyses may help its etiologic diagnosis earlier.Methods1. We collected21cases clinical data diagnosed with IHH from December2008toFebruary2013. Data include: age, main complain, sense of smell, intelligence, historyof familial and hereditary diseases, medication and surgical history, physical andsexual development, sex hormones level, karyotype, hCG and GnRH stimulating tests,bone age, ultrasound(sex gonads, pelvic and abdominal parts), MRI of pituitarygland and olfactory bulb.2. Polymerase Chain Reaction was applied and gene sequencing to detect mutationson KAL1and FGFR1.Result1. Clinical findings: Of21patients with IHH, social sex19males and2females, theyvisited us initially from8.00-17.00years old, with an average of13.58±2.38y.16cases are KS patients(76.2%).11patients accompanied abnormal sense of smellingand the olfactory organ abnormalities on MRI,4are olfactory organ abnormalities onMRI while they had good smelling function self-reportedly. There is one boy reportedabnormal sense of smelling but having olfactory perfect picture on MRI; the rest fivenIHH patients has normal sense of smelling and imagination investigation. Chiefcomplain of10out of19male cases is no sign of sexual development, but80%of them had small penis or/and cryptorchidism when they were young children: threeonly had small penis, four had both of cryptorchidism and small penis,1boy hadcryptorchidism combined with a normal penis. Two boys had no puberty when theyare over13-14years old without abnormal external genitalia. Another nine cases ofmale children visited us just for genital abnormal: five with simple micropenis andfour boys with micropenis combined with cryptorchidism, and the Case2also hadhypospadias. Only2girls diagnosed IHH who visited us because of no puberty signswhen13and16years old respectively. Other clinical manifestations include:2hadmental retardation, and one was deaf; one with gynecomastia, one with high palatalarch; one with mirror-movement and one with renal dysplasia respectively.Laboratory tests shows that karyotype of all patients are normal. The basictestosterone (T) is low and with inappropriately low or normal gonadotropinhormones. There are15patients with absent or hypoplasia of the olfactory bulb,olfactory tract or olfactory groove can be seen on the brain MRI among21cases，fourcases olfactory organ abnormalities on MRI while self-reported smelling functiongood, and one boy reported abnormal sense of smelling with normal olfactory onMRI.2Famliy history: the parents in9/21family have delayed puberty, involving only oneparents in6families, involving both in2families and the other1is an uncle havingmicropenis with a child. A father of1/21having hyposmia and first spermatorrheawas14-15years old.3. Gene test: We got15sampls（12KS and3nIHH cases）to screen the mutation ofKAL1(14exons) and FGFR1(18exons). A splicing mutation c.1062+1G>A in KAL1is identified in Case17with IHH. One novel heterozygous FGFR1mutationsa，asingle base deletion mutation on the exon1c.27delC is identified in case14. Thismutation causes the premature termination codons. Conclusions1.This pilot research shows that IHH/KS diagnosis in children depends on clinicalrather than gene analysis. Small penis or cryptorchidism, smelling abnormal andpositive familial history may contribute to the KS/HH diagnosis.2. High rates of familial history of CDGP suggested that CDGP may be variant typeof IHH.3. MRI of olfactory bulb acts as important proof for diagnosis of KS while diagnosingHH for non-KS patients (nIHH) remains a challenge.4. Mutations in KAL1and FGFR1gene are not main causes of Kallmann syndrome,with a positive rate of only6.67%(1/15).

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