Constitutional Delay Of Puberty Research Articles

Contributions of common genetic variants to constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism.

Constitutional delay of puberty (CDP) is highly heritable, but the genetic basis for CDP is largely unknown. Idiopathic hypogonadotropic hypogonadism (IHH) can be caused by rare genetic variants, but in about half of cases, no rare-variant cause is found. To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH. Case-control study. 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome; control genotyping data from unrelated studies. Polygenic scores (PGS) based on genome-wide association studies for timing of male pubertal hallmarks and age at menarche (AAM). The CDP cohort had higher PGS for male pubertal hallmarks and for AAM compared to controls (for male hallmarks, Cohen's d = 0.85, p = 1 × 10-16; for AAM, d = 0.67, p = 1 × 10-10). The normosmic IHH cohort also had higher PGS for male hallmarks compared to controls, but the difference was smaller (male hallmarks d = 0.20, p = 0.003; AAM d = 0.10, p = 0.055). No differences were seen for the KS cohort compared to controls (male hallmarks d = 0.04, p = 0.45; AAM d = -0.03, p = 0.86). Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, weakly to normosmic IHH, and potentially not at all to KS. These findings demonstrate that the common-variant genetics of CDP and normosmic IHH are largely but not entirely distinct.

THU206 Constitutional Delay Of Puberty And Idiopathic Hypogonadotropic Hypogonadism: Differential Contributions Of Common Genetic Variants

Abstract Disclosure: M.F. Lippincott: None. E. Schafer: None. A.A. Hindman: None. R. Brauner: None. A. Delaney: None. K. McElreavey: None. J.E. Hall: None. J.N. Hirschhorn: None. M.R. Palmert: None. S.B. Seminara: None. R.M. Salem: None. Y. Chan: None. Introduction: Disorders of pubertal timing include self-limited constitutional delay of puberty (CDP) and longer lasting idiopathic hypogonadotropic hypogonadism (IHH). Both conditions have strong genetic influences. We sought to determine if common genetic variants that influence pubertal timing contribute to CDP and IHH. Hypothesis: IHH and CDP can sometimes be caused by the accumulation of common genetic variants that delay pubertal onset. Therefore, compared to controls, patients with CDP and IHH have higher polygenic risk scores (PRS) based on genome-wide association studies (GWAS) for pubertal timing. Methods: All research and data-sharing were conducted with participant/guardian consent and institutional ethical approval. We defined CDP as puberty starting between 12 and 18 y in girls and between 13.5 and 18 y in boys and IHH as low sex steroids and non-elevated gonadotropins at ≥18 y, both with no cause identified on standard clinical evaluation. We genotyped CDP cases (n=106) on the Illumina Infinium OmniExpress Exome 8-1v6 platform and retrieved array-matched control data from dbGaP (n=9,222). IHH cases (n=713) and controls from the Schizophrenia Psychiatric GWAS (n=1,868) were genotyped on the Infinium PsychArray. After data harmonization, quality control, and principal components analysis were performed on combined sets, genotype imputation was performed on all unrelated individuals of European ancestry using the Michigan Imputation Server. We downloaded summary statistics for: 1) GWAS meta-analysis for age at menarche (AAM), 2) multi-trait GWAS for male pubertal hallmarks, and 3) a negative control using GWAS for basal cell carcinoma (BCC). We calculated and compared PRS between cases and controls using PRS-CS and PRSice2, with the first 10 ancestral principal components and sex as covariates. We also performed sex-stratified analyses. Results: Both the CDP and the IHH cohorts had significantly higher PRS for male pubertal hallmarks compared to controls, but the difference was smaller for IHH (CDP Cohen’s d=0.59, p=2×10-10; IHH d=0.13, p=0.007). The CDP cohort also had a significantly higher PRS for AAM compared to controls (d=0.83, p=8×10-20), but the IHH cohort did not (d=0.08, p=0.06). Of note, sex-specific PRS provided greater discrimination between CDP cases and controls in stratified analyses of the corresponding sex (AAM in females: d=1.1, p=4×10-11; AAM in males d=0.72, p=8×10-11; male hallmarks in females: d=0.52, p=0.001; male hallmarks in males: d=0.63, p=2×10-8). No significant differences were observed between cases and controls for BCC PRS. Conclusions: Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, with some sex-specificity, but only weakly to IHH. These findings support the hypothesis that the common-variant genetics of CDP and IHH are largely distinct. Presentation: Thursday, June 15, 2023

Clinical “Red Flags” Differentiating Delayed Puberty From Enduring Hypogonadism

Delayed puberty affects between 2% and 3% of the population and is a common reason for seeking endocrine consultation. Evaluation involves ruling out pathologic functional conditions disrupting puberty. Adolescents with constitutional delay of puberty (CDP) will initiate puberty spontaneously, albeit later than peers. However, some individuals have congenital hypogonadotropic hypogonadism (CHH) and will neither initiate nor progress in pubertal development. No single gold standard test differentiates CDP from CHH, posing diagnostic challenges for clinicians. This report provides an overview of normal/disrupted puberty, highlights clinical “red flags” facilitating identification of CHH, and emphasizes comprehensive and interprofessional approaches to care.

The use of stimulation tests for the differential diagnosis of delayed puberty in boys. How to increase the specificity of the method?

BACKGROUND: In patients with a constitutional delay of puberty starts and ends completely without any medical intervention. In adolescents with hypogonadotropic hypogonadism puberty is absent or does not continue its development. Differential diagnosis of the conditions is complicated due to lack of standard recommendations for the selection, conducting and assessment of stimulation tests.
 AIM: To assess the information content and find ways to increase the specificity of stimulation tests with triptorelin and corionic gonadotropin in relation to hypogonadotropic hypogonadism.
 MATERIALS AND METHODS: We examined 44 adolescent boys aged 13.517 years with delayed puberty. Sexual development was assessed according to Tanner scale, bone age (X-ray of the non-dominant hand according to the Greulich atlas). All boys were tested with triptorelin. The test with one- and three-day intramuscular injection of human chorionic gonadotropin was performed in 26 and 35 patients, respectively. Statistical analysis was performed using the StatTech v. 2.6.1 (developer Stattech LLC, Russia). To assess the diagnostic significance of quantitative signs in predicting a certain outcome the ROC-curve analysis was performed.
 RESULTS: It was revealed that a negative test with triptorelin was observed in some patients with constitutional delay of puberty. Threshold stimulated luteinizing hormone and follicle stimulating hormone levels were set (8.90 and 5.90 IU/l respectively). Gonadotropins values equal to or lower than selected thresholds allow diagnosing of hypogonadotropic hypogonadism with high sensitivity and specificity. Threshold testosterone levels stimulated by one- and three-day administration of human chorionic gonadotropin were determined (2.11 and 5.84 nmol/l respectively). Testosterone values equal to or lower than selected thresholds allow diagnosing of hypogonadotropic hypogonadism with high sensitivity and specificity. A high degree of positive correlation was found between stimulated luteinizing hormone levels and stimulated testosterone levels during a three-day test with human chorionic gonadotropin.
 CONCLUSIONS: A negative test with triptorelin is observed in some patients with constitutional delay of puberty. The specificity of the test can be improved by using threshold stimulated levels of luteinizing hormone and follicle stimulating hormone (8.90 and 5.90 IU/L, respectively). The use of the threshold levels of testosterone (2.11 and 5.84 nmol/l within the one- and three-day functional tests of the testicles respectively) can help to increase the specificity of the considered outdated stimulation tests with human chorionic gonadotropin.

Unravelling a novel, promising and convenient tool for differential diagnosis of delayed puberty: GnRHa-stimulated inhibin B (GnRH-iB)

Etiological diagnosis of delayed puberty is difficult. Despite availability of various basal and stimulation tests differentiation between constitutional delay in puberty and hypogonadotropic hypogonadism is still challenging. To elucidate the role of GnRH agonist-stimulated inhibin B (GnRH-iB) for the differential diagnosis of delayed puberty. Participants were recruited into "exploratory cohort" (n = 39) and "validation cohort" (n = 16). "Exploratory cohort" included children with spontaneous puberty and patients with hypogonadotropic hypogonadism. "Validation cohort" constituted children who presented with delayed puberty. GnRHa (Triptorelin) stimulation test along with measurement of inhibin B level at 24h after GnRHa injection was performed in all the study participants. Cut-offs for GnRH-iB were derived from the "exploratory cohort". These cut-offs were applied to the "validation cohort". Basal LH, basal inhibin B(INH-B), GnRHa-stimulated LH at 4h (GnRH-LH) and GnRH-iB were evaluated for the prediction of onset of puberty on prospective follow-up. GnRH-iB at a cut-off value of 113.5pg/ml in boys and 72.6pg/ml in girls had 100% sensitivity and specificity for the documentation of puberty. In the "validation cohort" basal LH, basal INH-B, GnRH-LH, and GnRH-iB had a diagnostic accuracy of 68.75%, 81.25%, 68.75% and 93.75% respectively, for the prediction of onset of puberty. Basal LH, basal INH-B and GnRH-LH used alone or in combination were inferior to GnRH-iB used alone. GnRHa-stimulated inhibin B (GnRH-iB) is a convenient and easily employable test for the differentiation of constitutional delay in puberty from hypogonadotropic hypogonadism. CTRI/2019/10/021570.

Recent advancement in the treatment of boys and adolescents with hypogonadism.

Clinical manifestations and the need for treatment varies according to age in males with hypogonadism. Early foetal-onset hypogonadism results in disorders of sex development (DSD) presenting with undervirilised genitalia whereas hypogonadism established later in foetal life presents with micropenis, cryptorchidism and/or micro-orchidism. After the period of neonatal activation of the gonadal axis has waned, the diagnosis of hypogonadism is challenging because androgen deficiency is not apparent until the age of puberty. Then, the differential diagnosis between constitutional delay of puberty and central hypogonadism may be difficult. During infancy and childhood, treatment is usually sought because of micropenis and/or cryptorchidism, whereas lack of pubertal development and relative short stature are the main complaints in teenagers. Testosterone therapy has been the standard, although off-label, in the vast majority of cases. However, more recently alternative therapies have been tested: aromatase inhibitors to induce the hypothalamic-pituitary-testicular axis in boys with constitutional delay of puberty and replacement with GnRH or gonadotrophins in those with central hypogonadism. Furthermore, follicle-stimulating hormone (FSH) priming prior to hCG or luteinizing hormone (LH) treatment seems effective to induce an enhanced testicular enlargement. Although the rationale for gonadotrophin or GnRH treatment is based on mimicking normal physiology, long-term results are still needed to assess their impact on adult fertility.

Androgen Treatment in Adolescent Males With Hypogonadism.

During adolescence, androgens are responsible for the development of secondary sexual characteristics, pubertal growth, and the anabolic effects on bone and muscle mass. Testosterone is the most abundant testicular androgen, but some effects are mediated by its conversion to the more potent androgen dihydrotestosterone (DHT) or to estradiol. Androgen deficiency, requiring replacement therapy, may occur due to a primary testicular failure or secondary to a hypothalamic–pituitary disorder. A very frequent condition characterized by a late activation of the gonadal axis that may also need androgen treatment is constitutional delay of puberty. Of the several testosterone or DHT formulations commercially available, very few are employed, and none is marketed for its use in adolescents. The most frequently used androgen therapy is based on the intramuscular administration of testosterone enanthate or cypionate every 3 to 4 weeks, with initially low doses. These are progressively increased during several months or years, in order to mimic the physiology of puberty, until adult doses are attained. Scarce experience exists with oral or transdermal formulations. Preparations containing DHT, which are not widely available, are preferred in specific conditions. Oxandrolone, a non-aromatizable drug with higher anabolic than androgenic effects, has been used in adolescents with preserved testosterone production, like Klinefelter syndrome, with positive effects on cardiometabolic health and visual, motor, and psychosocial functions. The usual protocols applied for androgen therapy in boys and adolescents are discussed.

Normosmic idiopathic hypogonadotropic hypogonadism due to a novel GNRH1 variant in two siblings.

SummaryHypogonadotropic hypogonadism is characterised by insufficient secretion of pituitary gonadotropins resulting in delayed puberty, anovulation and azoospermia. When hypogonadotropic hypogonadism occurs in the absence of structural or functional lesions of the hypothalamic or pituitary gland, the hypogonadism is defined as idiopathic hypogonadotropic hypogonadism (IHH). This is a rare genetic disorder caused by a defect in the secretion of gonadotropin releasing hormone (GNRH) by the hypothalamus or a defect in the action of GNRH on the pituitary gland. Up to 50% of IHH cases have identifiable pathogenic variants in the currently known genes. Pathogenic variants in the GNRHR gene encoding the GNRH receptor are a relatively common cause of normosmic IHH, but reports of pathogenic variants in GNRH1 encoding GNRH are exceedingly rare. We present a case of two siblings born to consanguineous parents who were found to have normosmic idiopathic hypogonadotropic hypogonadism due to homozygosity of a novel loss-of function variant in GNRH1. Case 1 is a male who presented at the age of 17 years with delayed puberty and under-virilised genitalia. Case 2 is a female who presented at the age of 16 years with delayed puberty and primary amenorrhea.Learning points:IHH is a genetically heterogeneous disorder which can be caused by pathogenic variants affecting proteins involved in the pulsatile gonadotropin-releasing hormone release, action, or both.Currently known genetic defects account for up to 50% of all IHH cases. GNRH1 pathogenic variants are a rare cause of normosmic IHH.IHH is associated with a wide spectrum of clinical manifestations.IHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty.Early diagnosis and gonadotrophin therapy can prevent negative physical sequelae and mitigate psychological distress with the restoration of puberty and fertility in affected individuals.

Role of melatonin in constitutional delayed puberty in boys

Objective The aim of this work to assess melatonin level in boys with constitutional delayed puberty (CDP) and study its correlation to follicle-stimulating hormone (FSH), total testosterone, and prolactin hormones. Background CDP is a common cause of pubertal delay. These boys have no underlying pathology and will progress normally. Melatonin hormone has an important role in pubertal onset. Before puberty, it is too high for hypothalamic activation. However, at puberty, it drop below threshold value, after which pubertal changes start occurring. Patients and methods This study was carried out on 50 boys aged 14–18 years who were divided into two groups: 25 boys with CDP as a patient group and another 25 age-matched boys with full pubertal development as a control group. All boys were subjected to full history taking, clinical examination, bone age determination, and laboratory investigations (testosterone, FSH, prolactin, and melatonin). Results Our results showed that in CDP, bone age is significantly delayed compared with their chronological age as well as the bone age of control group. Weight and height are significantly less in CDP than control. Both serum total testosterone and FSH are significantly lower in CDP compared with controls, whereas there were insignificant differences in serum prolactin. Melatonin is significantly higher in CDP compared with control. Melatonin is inversely correlated with both testosterone and FSH and has no correlation with prolactin. Conclusion Melatonin is significantly elevated in CDP boys, and it is negatively correlated with hormones of sexual maturation (testosterone) and reproduction (FSH).

Evaluation and management of amenorrhea related to congenital sex hormonal disorders.

Primary amenorrhea is a symptom with a substantial list of underlying etiologies which presents in adolescence, although some conditions are diagnosed in childhood. Primary amenorrhea is defined as not having menarche until 15 years of age (or 13 years with secondary sex characteristics). Various etiologies of primary amenorrhea include outflow tract obstructions, gonadal dysgenesis, abnormalities of the central nervous system, various endocrine diseases, chronic illnesses, psychologic problems, and constitutional delay of puberty. The management of primary amenorrhea may vary considerably depending on the patient and the specific diagnosis. In this article, the various causes, evaluation, and management of primary amenorrhea are reviewed with special emphasis on congenital sex hormonal disorders.

DELAYED PUBERTY IN BOYS. MODERN ASPECTS

Pubertal impairment in adolescents is an urgent pediatric problem conditioned by progressive worsening of the population’s reproductive health in general. One of the variants of teenagers’ puberty disturbances is the delayed puberty (DP) as no secondary sexual maturation by the age of 14 years in boys. There are discriminated hypogonadism and constitutional DP, the latter being the most frequent form of the disorder of pubertal development in boys, accounting for 60-80% of all forms of DP. At the base of pathogenesis of constitutional DP there are lied deteriorations in the system of the regulation of impulse secretion of gonadotrophin-releasing hormone (Gn-RH) and such non-hormonal factors as monamines of adrenergic and dophaminergic system, melatonin, neuropeptide Y, estragens, insulin-like growth factor-1 (IGF-1), leptine, interacting with Gn-RH-secreting neurons. Pathology of the development and maturation of structures of the diencephalon, as the cause of constitutional APD, is a rather frequent consequence of antenatal and perinatal pathology, traumatic injury of the brain, microcirculatory disorders. DP proves to be an unfavorable factor in the formation of bone density and final growth, in psychological personality achievement of the adolescent, in the maturation of the reproductive system, thus is the subject to correct. The problem of the therapy of constitutional puberty arrest remains to be controversial up to recent time. Some authors adhere to the observation tactics. They believe that children with constitutional DP may have a favorable prognosis of final growth and pubertal development. However, obvious negative psychosocial and medical consequences of the delayed growth and puberty have not yet been taken into consideration. Lately, hormonal therapy with puberty-stimulating steroids, anabolic agents has been suggested. But both a number of questions concerning the effect of therapy with androgens on activation of the hypophyseal-gonadal system in adolescents, and the impact of this treatment on the final growth of the patients remain to be unsolved. The necessity to produce an effect on central mechanisms of regulation by applying physiotherapeutic transcranial techniques, particularly transcranial magnetic therapy also exists. The presented review showed the diversity of factors influencing on the pubertal development of adolescents, various tactical methods of treatment and correction of disorders in patients with constitutional PD.

A de novo KMT2D mutation in a girl with Kabuki syndrome associated with endocrine symptoms: a case report

BackgroundKabuki syndrome is characterized by distinctive facial features and varying degrees of growth retardation. It leads to malformations in skeletal, urogenital and cardiac structures; moreover, endocrine conditions such as premature thelarche, precocious puberty, growth hormone deficiency, diabetes insipidus, thyroid dysfunction and obesity have been reported. Kabuki syndrome is caused by a heterozygous mutation in the KMT2D or KDM6A genes.Case presentationAn 11-year-old girl with the typical facial features of Kabuki syndrome visited our hospital due to her short stature. She was found to have the de novo heterozygous mutation of c.8200C > T, p(Arg2734*) in exon 32 of the KMT2D gene and was diagnosed with Kabuki syndrome. The patient also exhibited endocrine abnormalities such as a constitutional delay of puberty, transiently congenial hypothyroidism, obesity and growth hormone deficiency.ConclusionsThis is a case of a mutation in the KMT2D gene in a girl with Kabuki syndrome who presented with endocrine symptoms (constitutional delay of puberty, hypothyroidism, obesity and growth hormone deficiency).

Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism

Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (IGD) IGD is a genetically and clinically heterogeneous disorder. Mutations in many different genes are able to explain ~40% of the causes of IGD, with the rest of cases remaining genetically uncharacterized. While most mutations are inherited in X-linked, autosomal dominant, or autosomal recessive pattern, several IGD genes are shown to interact with each other in an oligogenic manner. In addition, while the genes involved in the pathogenesis of IGD act on either neurodevelopmental or neuroendocrine pathways, a subset of genes are involved in both pathways, acting as “overlap genes”. Thus, some IGD genes play the role of the modifier genes or “second hits”, providing an explanation for incomplete penetrance and variable expressivity associated with some IGD mutations.The clinical spectrum of IGD includes a variety of disorders including Kallmann Syndrome (KS), i.e. hypogonadotropic hypogonadism with anosmia, and its normosmic variation normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which represent the most severe aspects of the disorder. Apart from these disorders, there are also “milder” and more common reproductive diseases associated with IGD, including hypothalamic amenorrhea (HA), constitutional delay of puberty (CDP) and adult-onset hypogonadotropic hypogonadism (AHH). Interestingly, neurodeveloplmental genes are associated with the KS form of IGD, due to the topographical link between the GnRH neurons and the olfactory placode. On the other hand, neuroendocrine genes are mostly linked to nIHH. However, a great deal of clinical and genetic overlap characterizes the spectrum of the IGD disorders. IGD is also characterized by a wide variety of non-reproductive features, including midline facial defects such as cleft lip and/or palate, renal agenesis, short metacarpals and other bone abnormalities, hearing loss, synkinesia, eye movement abnormalities, poor balance due to cerebellar ataxia, etc. Therefore, genetic screening should be offered in patients with IGD, as it can provide valuable information for genetic counseling and further understanding of IGD.

Silent Crooke's cell corticotroph adenoma of the pituitary gland presenting as delayed puberty.

SummaryCorticotroph adenomas are extremely rare in children and adolescents. We present a 15-year-old boy who was investigated for delayed puberty (A1P2G1, bilateral testicular volumes of 3 mL each). There was no clinical or laboratory evidence suggestive of chronic illness, and the initial clinical impression was constitutional delay in puberty. Subsequently, MRI scan of the brain revealed the presence of a mixed cystic and solid pituitary lesion slightly displacing the optic chiasma. The lesion was removed by transphenoidal surgery and the biopsy confirmed the lesion to be pituitary adenoma. Furthermore, the adenoma cells also had Crooke’s hyaline changes and were intensely positive for ACTH. However there was no clinical/biochemical evidence of ACTH excess. There was a spontaneous pubertal progression twelve months after the surgery (A2P4G4, with bilateral testicular volume of 8 mL). Crooke’s cell adenoma is an extremely rare and aggressive variant of corticotroph adenoma that can uncommonly present as a silent corticotroph adenoma in adults. We report for the first time Crooke’s cell adenoma in an adolescent boy presenting with delayed puberty.Learning points:Constitutional delay of growth and puberty (CDGP) is a diagnosis of exclusion; hence a systematic and careful review should be undertaken while assessing boys with delayed puberty.Crooke’s cell adenomas are a group of corticotroph adenomas that can rarely present in childhood and adolescence with delayed puberty.Crooke’s cell adenomas can be clinically silent but are potentially aggressive tumours that require careful monitoring.

Diagnostic utility of testosterone priming prior to dynamic tests to differentiate constitutional delay in puberty from isolated hypogonadotropic hypogonadism.

Differentiation between constitutional delay in puberty (CDP) and isolated hypogonadotropic hypogonadism (IHH) during adolescence is a great clinical challenge, and the available diagnostic tests are of limited value. To study the effect of withdrawal of short-term, low-dose testosterone therapy (testosterone priming) on the discriminatory power of dynamic tests for hypothalamo-pituitary-testicular axis to differentiate CDP from IHH. A prospective study (n = 30) consisting of 20 boys with delayed puberty (group A) and 10 patients with IHH (group B). Patients in groups A and B underwent Triptorelin and hCG stimulation tests, prior to and 2 months after withdrawal of 'testosterone priming' (100 mg intramuscularly 4 weekly for 3 months) and were followed up until the onset of puberty or 18 years of age, whichever was earlier. At baseline, Triptorelin-stimulated 4 h LH, with a cut-off of 2·8 IU/l, and hCG-stimulated day 7 testosterone with a cut-off of 3·8 nmol/l had sensitivities of 80% each, and specificities of 93% and 87%, respectively, to diagnose CDP. After withdrawal of testosterone, a 4 h LH cut-off of 14·7 IU/l and day 7 testosterone cut-off of 10·3 nmol/l had sensitivities of 93% and 88% respectively, and specificity and positive predictive value of 100% each. A basal inhibin B > 94·7 ng/l was discriminatory for diagnosing CDP after withdrawal of testosterone priming. Inhibin B levels or 4 h LH after Triptorelin stimulation are the best discriminatory tests to differentiate CDP from IHH, when performed after withdrawal of 'testosterone priming'.

Constitutional delay of puberty: presentation and inheritance pattern in 48 familial cases.

BackgroundThe mechanism that initiates the onset of puberty is largely unknown but the age of onset is mainly under genetic control and influenced by environmental factors including nutrition. Familial forms of constitutional delay of puberty (CDP) suggest the involvement of genetic factors. The purpose of this study is to describe the presentation and the mode of inheritance of CDP in a series of familial cases.MethodsA retrospective, single center study was carried out over 10 years on 48 probands (14 girls and 34 boys) from 48 families seen for CDP with a familial component.ResultsOf the 48 probands, 46 (96 %) had at least one affected 1st degree relatives and 2 (4 %, 2 boys) had only 2nd degree relatives affected.In girls, 11 families (79 %) exhibited exclusive maternal inheritance, 1 (7 %) paternal inheritance and 2 (14 %) both maternal and paternal inheritance. In boys, 14 families (41 %) exhibited exclusive maternal inheritance, 12 (35 %) paternal inheritance and 8 (24 %) both maternal and paternal inheritance.In the boys with bilineal inheritance, the ages at onset of puberty (16 ± 1.41 years) and at evaluation (16.05 ± 2.47 years) were higher than in those with unilineal inheritance (15.25 ± 0.35 and 15.1 ± 0.42 years respectively), but the difference was not significant.ConclusionsIn girls exclusive maternal inheritance seems to be the major mode of inheritance whereas for boys the mode of inheritance was almost equally maternal, paternal or bilineal. Clinical phenotype of boys with bilineal inheritance seems to be more severe, but the difference did not reach statistical significance, perhaps because of the small sample size. This greater severity of the phenotype in boys with bilineal inheritance is likely due to inheriting different puberty timing genes from each parent. Future research should be directed at identifying such genes.

Genetics of Hypogonadotropic Hypogonadism.

Hypogonadotropic hypogonadism (HH) often manifests as pubertal delay. A considerable proportion of cases of HH is due to genetic mutations. Recognizing those mutated genes and associated phenotypes may improve our diagnostic capabilities. GNRHR and TACR3 should be the first two genes to be screened in a clinical setting for equivocal cases such as constitutional delay in puberty versus idiopathic HH. In Kallmann syndrome (KS), according to the presence of certain accompanying clinical features, genetic screening for particular gene(s) may be prioritized: synkinesia (KAL1), dental agenesis (FGF8/FGFR1), bony anomalies (FGF8/FGFR1), and hearing loss (CHD7, SOX10). FEZF1 has recently been added to the growing list of KS genes. Also, discovery of mutations in KISS1/KISS1R and TAC3/TACR3 in kisspeptin and neurokinin B signaling, respectively, has provided major advancements in our understanding of the biology of the gonadotropin-releasing hormone pulse generator. Identification of further causative mutations accounting for the HH phenotype, which is now more feasible with the increasing popularity of whole exome sequencing, may provide deeper insight into the biology of the hypothalamic-pituitary-gonadal axis.

Different Medications for Hypogonadotropic Hypogonadism.

Delayed puberty (DP) in boys is the lack of sexual maturation at a chronological age of 14 years. Several conditions induce DP and they can be classified into reversible and irreversible causes. The most common cause of DP is constitutional delay of puberty (CDP; 63%), followed by DPs due to functional hypogonadotropic hypogonadism (HH; 20%), congenital isolated HH (9%) and hypergonadotropic hypogonadism (7%). A correct diagnosis, although often difficult, is pivotal for choosing the most adequate therapy. In CDP boys, expectant management can be an option. However, patient's psychological distress can be attenuated by short-term low-dose testosterone therapy, which can induce male secondary sexual characteristics. When therapy is discontinued in CDP, pubertal development continues similarly to normal boys. Long-term testosterone therapy is the only option in boys with DP due to hypergonadotropic hypogonadism, whereas in subjects with HH, besides long-term testosterone, also gonadotropins and gonadotropin-releasing hormone (GnRH) can be used. Gonadotropins and GnRH, besides inducing secondary sexual characteristics, can also induce testicular maturation and spermatogenesis. Other molecules, such as kisspeptin and neurokinin B agonists, are now under evaluation as new therapeutic options for treating DP.

Aromatase Inhibitors in the Treatment of Short Stature.

Reports published in the 1990s of men with estrogen deficiency caused by defective aromatase or estrogen resistance due to a defective estrogen receptor α confirmed the crucial role of estrogen in bone maturation, closure of the epiphyses and cessation of statural growth. Based on these findings, it became reasonable to postulate that selective inhibition of estrogen synthesis with aromatase inhibitors could increase adult height by delaying bone maturation and prolonging the period of growth in males. To date, aromatase inhibitors have been employed in rare pediatric conditions associated with sex steroid excess, and in randomized controlled trials involving boys with short stature and/or constitutional delay of puberty. Findings from these randomized trials suggest that potent aromatase inhibitors increase predicted height, but final adult height data are scarce. Moreover, several safety issues remain inadequately studied. In this paper, published findings on the use of aromatase inhibitors in growth indications are reviewed with emphasis on treatment efficacy and safety.

AB158. A total of 213 cases with male isolated gonadotropin-releasing hormone deficiency: clinical feature analysis and gene mutation study in some cases.

ObjectiveIsolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a rare clinical condition with a broad spectrum of human reproductive disorders which varies from congenital isolated hypogonadotropic hypogonadism (IHH) to constitutional delay of puberty (CDP) and adult-onset isolated hypogonadotropic hypogonadism (AHH) in male. In the presence of anosmia or hyposmia, IHH is defined as Kallmann syndrome (KS), whereas in the presence of a normal sense of smell, it is termed normosmic IHH (nIHH). In this study, we described the clinical features of 213 Chinese IGD males, and performed genetic study in some of these cases, and analyzed their genotype phenotype correlations.MethodsWe collected the male isolated GnRH deficiency patients in our outpatient and filed their medical and family history. The physical examinations, laboratory and imaging studies were performed. The PCR and agarose gel electrophoresis, whole genome chip and semiconductor target areas sequencing were used to reveal the molecular defects of two KS and ichthyosis brothers. We also used semiconductor target areas sequencing and Sanger sequencing to detect the mutations in 15 IHH causative genes in 4 KS patients with cleft lip/palate (CLP) and 8 IGD patients (including 5 KS patients, one nIHH patients and two AIHH patients) without CLP. Functional prediction and conservation analysis were performed to predict the consequence of the three mutations.ResultsThe reproductive phenotypes in the IHH patients included Gynecomastia (23/210), microphallus (42/210), cryptorchidism (21/210), unilateral testicular agenesis (2/210), scrotum dysplasia (3/210). The non-reproductive phenotypes in our patients contained ichthyosis (3/210), unilateral renal agenesis (2/210), cleft lip (2/210), cleft lip and dental agenesis (1/210), cleft lip and palate combined with dental agenesis and high arched palate (1/210), nystagmus and iris hypoplasia (1/210). These non-reproductive phenotypes only presented in KS patients. The results of karyotype analysis showed that 15 out of the 210 IHH patients (7.1%) had polymorphic chromosomal variants.. The phenotypes of the two Chinese brothers with KS and X-linked ichthyosis were characterised by bilateral cryptorchidism, unilateral renal agenesis in one patient but normal kidney development in another. Genetic study showed that the two affected siblings had the same novel deletion at Xp22.3 including exons 9-14 of KAL1 gene and entire STS gene. We also identified two novel heterozygous missense mutations in FGFR1, (NM_001174066): c.776G>A (p.G259E) and (NM_001174066): c.358C>T (p.R120C), in a 23-yr-old KS male with cleft lip and an 18-year-old KS patient with cleft lip and palate, dental agenesis and high arched palate, respectively. By the way, one heterozygous missense mutation in KISS1R which was reported previously, (NM_032551): c.587C>A (p.P196H), was identified in an 18-yr-old KS male with cleft lip and dental agenesis. All the mutations were not presented in any of the 200 unrelated normal controls. However, we proved the KISS1R c.587C>A mutation was presented in the father and grandfather of the patients.ConclusionsOur study expanded the clinical phenotype and gene mutation spectrum of Chinese IGD patients and has implications for the genetic diagnoses and counseling of IGD.