Are Klinefelter boys hypogonadal?

Male hypogonadism implies decreased function of one or more testicular cell population, i.e. germ, Leydig and/or Sertoli cells. In the normal prepubertal boy, Sertoli cells are very active, as indicated by high anti-Müllerian hormone (AMH) and inhibin B secretion, whereas the functional activity of Leydig cells is minimal, as evidenced by low testosterone production, and germ cells do not undergo the full spermatogenic process. Klinefelter syndrome is the most frequent cause of hypogonadism in the adult male. In this review, we discuss whether the gonadal failure is already established during infancy and childhood. In Klinefelter syndrome, there is increased germ cells degeneration from mid-foetal life - resulting in a decreased number at birth - which persists during infancy and childhood and becomes dramatic during puberty. Controversial results exist in the literature regarding Leydig cell function in Klinefelter boys: while some authors have found normal to low testosterone levels in infancy and childhood, others have reported normal to high values. Sertoli cell products AMH and inhibin B are normal in prepubertal boys and only decline during mid- to late puberty. CONCLUSION: Klinefelter syndrome is a primary hypogonadism affecting all testicular cell populations. Germ cells are affected from foetal life, and a severe depletion occurs at puberty. Leydig cell function may be normal or mildly affected in foetal and early postnatal life. Sertoli cell function is not impaired until mid- to late puberty, as reflected by normal AMH and inhibin B in Klinefelter boys.     

48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome

Sex chromosome tetrasomy and pentasomy conditions occur in 1:18,000-1:100,000 male births. While often compared with 47,XXY/Klinefelter syndrome because of shared features including tall stature and hypergonadotropic hypogonadism, 48,XXYY, 48,XXXY and 49,XXXXY syndromes are associated with additional physical findings, congenital malformations, medical problems and psychological features. While the spectrum of cognitive abilities extends much higher than originally described, developmental delays, cognitive impairments and behavioural disorders are common and require strong treatment plans. Future research should focus on genotype-phenotype relationships and the development of evidence-based treatments. CONCLUSION: The more complex physical, medical and psychological phenotypes of 48,XXYY, 48,XXXY and 49,XXXXY syndromes make distinction from 47,XXY important; however, all of these conditions share features of hypergonadotropic hypogonadism and the need for increased awareness, biomedical research and the development of evidence-based treatments.     

Treatment situation of male hypogonadotropic hypogonadism in pediatrics and proposal of testosterone and gonadotropins replacement therapy protocols

Male hypogonadotropic hypogonadism (MHH), a disorder associated with infertility, is treated with testosterone replacement therapy (TRT) and/or gonadotropins replacement therapy (GRT) (TRT and GRT, together with HRT hormone replacement therapy). In Japan, guidelines have been set for treatment during adolescence. Due to the risk of rapid maturation of bone age, low doses of testosterone or gonadotropins have been used. However, the optimal timing and methods of therapeutic intervention have not yet been established. The objective of this study was to investigate the current situation of treatment for children with MHH in Japan and to review a primary survey involving councilors of the Japanese Society for Pediatric Endocrinology and a secondary survey obtained from 26 facilities conducting HRT. The subjects were 55 patients with MHH who reached their adult height after HRT. The breakdown of the patients is as follows: 7 patients with Kallmann syndrome, 6 patients with isolated gonadotropin deficiency, 18 patients with acquired hypopituitarism due to intracranial and pituitary tumor, 22 patients with classical idiopathic hypopituitarism due to breech delivery, and 2 patients with CHARGE syndrome. The mean age at the start of HRT was 15.7 yrs and mean height was 157.2 cm. The mean age at reaching adult height was 19.4 yrs, and the mean adult height was 171.0 cm. The starting age of HRT was later than the normal pubertal age and showed a significant negative correlation with pubertal height gain, but it showed no correlation with adult height. As for spermatogenesis, 76% of the above patients treated with hCG-rFSH combined therapy showed positive results, though ranging in levels; impaired spermatogenesis was observed in some with congenital MHH, and favorable spermatogenesis was observed in all with acquired MHH. From the above, we propose the establishment of a treatment protocol for the start low-dose testosterone or low-dose gonadotropins by dividing subjects into two groups to determine different treatment protocols, acquired and congenital MHH, and to conduct them at a timing closer to the onset of puberty, namely, at a timing near entrance to junior high school. We also propose a new HRT protocol using preemptive FSH therapy prior to GRT aimed at achieving future fertility in patients with congenital MHH.     

Morbidity and mortality in Klinefelter syndrome (47,XXY)

Klinefelter syndrome (KS) (47,XXY) is the most common sex chromosome disorder in man and is a relatively common cause of male infertility and hypogonadism. The syndrome has been known since 1942, and many reports of different diseases associated with KS have been reported since that, but a more systematic knowledge about the long-term outcome was not described until the last decade, where nation-wide epidemiological studies were reported from Britain and Denmark. We here review the epidemiological data from two cohorts of patients with KS in Denmark and Britain, showing a significant increase in both mortality and morbidity from a variety of different causes. Mortality was increased by 50% (SMR 1.5 or HR 1.4) corresponding to a median loss of approximately 2 years. The risk of being admitted to hospital with any diagnosis was increased by 70%. The underlying reason for the poorer health in KS may be caused by interaction of genetic, hormonal and socio-economic factors. CONCLUSION: Both morbidity and mortality are significantly increased in Klinefelter syndrome with a 50% increase in mortality risk and a 70% increase in risk of being admitted to hospital.     

Considerations for androgen therapy in children and adolescents with Klinefelter syndrome (47, XXY)

The goals of androgen therapy for adolescents are to promote linear growth and secondary sexual characteristics, at the same time as to permit the normal accrual of muscle mass, bone mineral content and the adult regional distribution of body fat. Secondary goals are mainly in the psychosocial sphere, in which pubertally delayed boys feel that they look too young, are not considered a 'peer' in their age group and have difficulty competing in athletic endeavors. Puberty often starts normally in adolescents with KS corresponding to the peer group with genital enlargement and pubic hair growth. The testes start to enlarge, but rarely expand beyond 6 mL, leaving a discordance between the degree of sexual development and the size of the testes. Androgen therapy is considered mainly supplemental and one usually begins with the long acting esters, testosterone enanthate or cypionate because the other forms patches and gels--are metered for full male replacement. The dose of testosterone is escalated until the lower range of the adult dose is reached and then a choice among the various forms can be made. Treatment-emergent adverse events often represent the pharmacodynamic effects of an androgen oily skin and acne, but as the dose is escalated more effects may be noted in the behavioral sphere, especially in adolescents with Klinefelter syndrome compared to those who receive replacement therapy with testosterone for other purposes, for example, constitutional delay of growth and puberty.     

Treatment of hypogonadal adolescent boys with long acting subcutaneous testosterone pellets

AIMS: Long acting subcutaneous testosterone pellets are of proved efficacy for the treatment of hypogonadal men, but have not been reported as a treatment modality in adolescent boys. Pharmacodynamic studies of subcutaneous testosterone release have shown prolonged normalisation of testosterone levels for at least four months. Administration of a long acting, safe, effective, and convenient form of treatment is desirable when life-long treatment is indicated. PATIENTS AND METHODS: Eighteen boys (aged 13.9-17.5 years at the start of treatment)-seven with primary hypogonadism, nine with secondary hypogonadism, and two boys being treated with testosterone for tall stature--were given testosterone pellets (8-10 mg/kg) every six months for 18 months. Height, weight, pubertal status, and psychosocial parameters were assessed and follicle stimulating hormone, luteinising hormone, testosterone, prolactin, and lipids were measured at 0, 1, 3, 6, 12, and 18 months. Bone age was measured at 0 and 12 months. RESULTS: In all boys growth velocity continued appropriately for bone age. Puberty continued to progress in all boys and in two boys the amount of virilisation exceeded that seen with previous treatment with intramuscular testosterone. After testosterone administration, follicle stimulating hormone and luteinising hormone suppressed incompletely in the boys with primary hypogonadism. Serum testosterone ranged from 4.3 to 26.7 nmol/l at three months to less than 10 nmol/l at six months after implantation. Prolactin and lipid levels were normal throughout the study. By report, there was an improvement in mood and emotional wellbeing. No pellet extrusions occurred in a total of 156 pellet insertions. CONCLUSIONS: All boys preferred this mode of testosterone administration to intramuscular injections. Long acting subcutaneous testosterone pellets are safe, efficacious, well tolerated, and convenient, and result in normal physical growth and improved psychological outlook in adolescent hypogonadal boys.     

Clinical and biological parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience

Aim: Klinefelter syndrome (KS) is the most frequent sex chromosome disorder in males, but the phenotype varies greatly and is therefore highly under‐diagnosed. We aimed at describing the phenotypic characteristics throughout life from clinical follow‐up of our large cohort of patients with KS. Methods: A retrospective observational study of 166 males with nonmosaic 47,XXY KS aged 0.3–80.3 years. Data on phenotype, growth, body composition, bone mineral density, sex hormones, lipids, glycosylated haemoglobin (HbA1C) and prostate‐specific antigen were recorded. In addition, histological examination of testicular biopsies from 29 patients was performed. Results: Patients with Klinefelter were taller already in childhood. All patients had smaller testicular volume and elevated luteinizing hormone (LH) and follicle‐stimulating hormone levels in adulthood. Cryptorchidism was reported in 14%, gynaecomastia in 44%, and 36% required speech therapy or educational support. The abnormal biochemical parameters became evident after onset of puberty and correlated with histological findings of a gradual deterioration of seminiferous tubules and massive Leydig cell hyperplasia in adults. Conclusion: Our patients presented with a wide spectrum of the classical Klinefelter symptoms. In adulthood, two features were consistently present in every patient: small testes and high LH/testosterone ratio, often despite normal testosterone levels. Such biochemical parameters combined with small testes should lead to a suspicion of KS.     

Bone density and risk of osteoporosis in Klinefelter syndrome

Different mechanisms in Klinefelter syndrome contribute to reduced bone mass and osteoporosis, which have a precocious onset and are detected in up to 40% of patients, irrespectively of testosterone levels. Androgen receptor, X chromosome inactivation and INSL3 levels are hypothesized to cooperate with and modulate the effect of testosterone on the bone. CONCLUSION: New perspectives on genetic topics are opening exciting areas of research on the pathophysiology of reduced bone mass in Klinefelter patients.     

Diagnosis of delayed puberty]

Puberty is the phenomenon that conducts once to reproductive maturation. Delayed puberty (DP) is defined by the absence of testicular development in boys beyond 14 years old (or a testicular volume lower than 4 ml) and by the absence of breast development in girls beyond 13 years old. DP occurs in approximatively 3% of cases. Most cases are functional DP, with a large amount of constitutional delay of puberty. Others etiologies are hypogonadotrophic hypogonadism like Kallmann syndrome, or hypergonadotrophic hypogonadism. Turner syndrome is a diagnostic one should not forget by its frequency. Treatment is hormonal replacement therapy and of the etiology. During the last decade, many genes have been identified and elucidated the etiological diagnosis of some hypogonadotrophic hypogonadism syndrome. Further studies are required in collaboration with molecular biologists to better understand the mechanism of hypothalamic pituitary gonadal axis abnormalities and of the neuroendocrine physiology of the onset of puberty.     

The adolescent and young adult with Klinefelter syndrome:ensuring successful transitions to adulthood

As many adolescent and young adult males with Klinefelter syndrome move into young adulthood, they will require long-term medical and mental health care for their complex and specific health care needs. Adult general medical providers and endocrinologists may feel ill-prepared to meet the medical needs of this population. In turn, many pediatric primary care and subspecialty providers may find themselves struggling to determine how best to transition the older adolescent to adult-oriented services. Working with families and their teens to consider and address current and future medical, mental health, educational and vocational needs will enhance that young adult's independence and functioning. This chapter addresses general transition issues and those that are specific to adolescents with Klinefelter syndrome. The prognosis for these young patients is good, and can be further enhanced by supportive families and a medical team that is informed about how best to facilitate the transition to adult-oriented services.     

Clinical experience using the Androderm testosterone transdermal system in hypogonadal adolescents and young men with beta-thalassemia major

beta-Thalassemia major is associated with a high prevalence of hypogonadotropic hypogonadism affecting adolescents and young men with this disease. The pharmacokinetics of Androderm, a non-scrotal permeation-enhanced testosterone transdermal system, was previously studied in this population using three application regimens designed to mimic the nocturnal secretion and circadian patterns of testosterone production characteristics of puberty and young adulthood. In regimen I, designed for prepubertal 14 to 16 year-olds, a single Androderm patch (2.5 mg/day nominal delivery rate) is applied at night and removed 12 hours later in the morning. In regimen II, designed for partially virilized 17 to 19 year-olds, a single Androderm patch is applied nightly for 24 hours. In regimen III, intended for virilized men aged 20 years and older, two Androderm patches (total dose of 5 mg/day) are applied nightly for 24 hours. This report presents the results of a 12-month open label study using these three Androderm regimens to treat nine hypogonadal males with beta-thalassemia (ages 16.8 to 31.8 yr). Our data show that Androderm produced physiologically appropriate testosterone levels, lowered SHBG levels, promoted growth and virilization, increased bone mineral density, and was generally well tolerated in this population of hypogonadal adolescents and young men with beta-thalassemia.     

男性特发性低促性腺激素型性腺功能减退症3例致病基因分析

目的 对3例特发性低促性腺激素型性腺功能减退症(IHH)患者进行致病基因检测,以探讨其可能存在的致病基因突变.方法 收集临床资料和血标本,并进行详细的实验室检查,采用FUJIFILM QuickGene-610L抽提外周血白细胞DNA,针对目前5个主要的Kallmann 综合征的致病基因和嗅觉正常的IHH(nIHH)致病基因[促性腺激素释放激素受体(GnRHR)基因]采用PCR扩增6个基因的全部外显子.PCR产物直接测序后,采用Auto Assemble 软件比对寻找突变.结果 2例患者诊断为Kallmann综合征,1例患者诊断为nIHH;基因测序结果发现,除了在2例患者中发现了位于内分泌腺源性血管内皮生长因子受体2(PROKR2)基因上的单核苷酸多态性改变外,3例患者均无Kallmann综合征1基因(KAL1),成纤维细胞生长因子受体1(FGFR1),PROKR2和内分泌腺源性血管内皮生长因子2(PROK2),成纤维细胞生长因子8(FGF8)基因的突变,1例nIHH患者也无GnRHR基因突变.结论 IHH是一种在临床和基因水平异质性疾病,对3例IHH患者排除了目前主要致病基因的突变,提示其他基因或致病因素参与此病的发生.     

Familial cytomegalic adrenocortical hypoplasia: an X-linked syndrome of pubertal failure.

Five boys with familial cytomegalic adrenocortical hypoplasia have been followed up for an average of 19 years. Despite treatment with replacement corticosteroids, all 5 failed to show a spontaneous onset of puberty and, when assessed at ages 13 to 19 years, all had both sexual infantilism and skeletal immaturity. Hypogonadism was confirmed by low levels of plasma testosterone, and pituitary reserve of gonadotrophin was shown to be inadequate by testing with gonadotrophin-releasing hormone. Two boys, both with adequate testosterone output on human chorionic gonadotrophin stimulation, were given gonadotrophin therapy, whereas the other 3 were treated with parenterally administered testosterone. With treatment, all 5 patients showed advances in pubertal staging. Although the mechanism of the hypogonadotropism remains unclear, the association of hypogonadotrophic hypogonadism with familial cytomegalic adrenocortical hypoplasia appears to be a constant one and may be considered as a treatable inherited syndrome of pubertal failure.     

Familial cytomegalic adrenocortical hypoplasia: an X-linked syndrome of pubertal failure

Five boys with familial cytomegalic adrenocortical hypoplasia have been followed up for an average of 19 years. Despite treatment with replacement corticosteroids, all 5 failed to show a spontaneous onset of puberty and, when assessed at ages 13 to 19 years, all had both sexual infantilism and skeletal immaturity. Hypogonadism was confirmed by low levels of plasma testosterone, and pituitary reserve of gonadotrophin was shown to be inadequate by testing with gonadotrophin-releasing hormone. Two boys, both with adequate testosterone output on human chorionic gonadotrophin stimulation, were given gonadotrophin therapy, whereas the other 3 were treated with parenterally administered testosterone. With treatment, all 5 patients showed advances in pubertal staging. Although the mechanism of the hypogonadotropism remains unclear, the association of hypogonadotrophic hypogonadism with familial cytomegalic adrenocortical hypoplasia appears to be a constant one and may be considered as a treatable inherited syndrome of pubertal failure.     

Delayed puberty due to a novel mutation in CHD7 causing CHARGE syndrome

We report the case of a 15-year-old girl who presented to a pediatric endocrinology clinic for delayed puberty with no signs of secondary sexual development. Her past medical history was significant for bilateral colobomas, inner-ear anomalies, hearing loss, and anosmia. Genetic testing revealed a novel de novo mutation in the CHD7 gene, one of the causative genes in CHARGE syndrome (coloboma, heart disease, choanal atresia, retarded growth and development and/or central nervous system anomalies, genital anomalies and/or hypogonadism, and ear anomalies and/or deafness). We review the distinction between hypogonadotrophic hypogonadism and hypergonadotrophic hypogonadism and discuss the availability of molecular genetic testing for idiopathic hypogonadotrophic hypogonadism. CHD7 mutations have also been found in some patients with Kallmann syndrome, hypogonadotrophic hypogonadism, and anosmia, and we discuss the overlap between this syndrome and CHARGE syndrome. With the increased availability of genetic testing for a variety of disorders, it is important for pediatricians to become familiar with interpreting genetic test results. Finally, we illustrate that Bayes' theorem is a useful statistical tool for interpreting novel missense mutations of unknown significance.     

Turner综合征的卵巢功能评估和激素替代治疗

特纳综合征（TS）通常有高促性腺激素性性腺功能减退症、 原发性或继发性闭经。因此， 大多数TS患者需要激素替代疗法（HRT）来诱导青春期， 维持第二性征发育，使子宫正常生长， 并获得峰值骨量。激素替代的目的是模拟正常的身心发育。诱导青春期发育的最佳激素替代治疗方案仍在不断的优化和改进。治疗应从11～12岁开始， 在2～3年内每6个月增加一次剂量。低剂量的雌激素启动青春期对于保护生长潜力至关重要。该文重点介绍了在TS年轻患者中的性激素替代疗法， 期望为临床医生提供实际帮助。     

Gonadal function and glycoprotein hormones in the carbohydrate-deficient glycoprotein (CDG) syndrome

Six females and six males with carbohydrate-deficient glycoprotein (CDG) syndrome type I, aged 4 months to 43 years, were examined for gonadal function and electrophoretic isoform patterns of four glycoprotein hormones: FSH, LH, TSH and erythropoietin. The female patients had a hypergonado-trophic hypogonadism from an early age without detectable ovaries in three cases. In the males, testosterone levels tended to be low with normal or slightly raised gonadotrophin values. None of the four glycoprotein hormone showed any signs of carbohydrate deficiency of the same type as in many liver-synthesized circulating glycoproteins. It is concluded that females with CDG syndrome type I have primary ovarian failure, and that the syndrome does not affect the terminal charged carbohydrate portion in gonadotrophins, TSH or erythropoietin. The characteristic carbohydrate deficiency in some circulating glycoproteins is thus not a generalized feature in this disease.     

Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome

Aims: To investigate risk factors for metabolic syndrome in prepubertal boys with Klinefelter syndrome. Methods: Eighty‐nine boys with Klinefelter syndrome, ages 4–12.9 years, and 34 age‐matched control boys had height, weight, waist circumference and blood pressure measured and their parents completed a questionnaire about physical activity. The boys with Klinefelter syndrome also had measurement of lipids, fasting glucose and insulin. Insulin‐glucose homeostasis model assessment was calculated, and the boys were evaluated for childhood metabolic syndrome. Results: The Klinefelter syndrome and control groups were similar ages (7.5 ± 2.4 vs. 8.1 ± 2.3 years). Body mass index measurements were similar, but waist circumference was >90 percentile in 30% of boys with Klinefelter syndrome versus 21% of controls. The mean daily time spent running was 42 min less in the Klinefelter syndrome versus control groups (p < 0.01). About 37% of the boys with Klinefelter syndrome had elevated LDL cholesterol, 24% had insulin resistance, and 7% met the three criteria for diagnosis of metabolic syndrome. Conclusions: Truncal obesity, insulin resistance and metabolic syndrome are present in boys as young as 4–12 years with Klinefelter syndrome, and these occur in association with reduced running‐type activity.     

The impact of concurrent X chromosome anomalies on diagnosis and bleeding phenotype in children with hemophilia: A single-institution case series

Hemophilia is an inherited X-linked bleeding disorder characterized by deficiencies of factors VIII or IX. Concomitant X chromosome disorders can impact bleeding phenotype, complicating timely diagnosis and disease management. Herein, we describe three cases of female and male pediatric patients with hemophilia A or B diagnosed between 6 days and 4 years old in the setting of skewed X chromosome inactivation, Turner syndrome, or Klinefelter syndrome. All of these cases had significant bleeding symptoms, and two patients required initiation of factor replacement therapy. One female patient developed a factor VIII inhibitor similar to that described in males with hemophilia A.