Humans ; Hypogonadism/drug therapy* ; Male ; Puberty ; Puberty, Delayed ; Treatment Outcome

A 26-year-old female presented to the paediatric clinic at 11 years of age with poor growth. The detection of delayed puberty, anosmia, coloboma and hearing impairment led to a diagnosis of CHARGE syndrome. This was confirmed by a heterogenous de novo pathogenic variant c.6955C >T:p.(Arg2319Cys) detected in the CHD7 gene. Detailed assessment, including olfaction, ophthalmic and auditory examination should be part of the evaluation framework in children with delayed growth and puberty.
Anosmia ; Puberty, Delayed

Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. Clinical presentations are similar, featured with typical facial features, short stature, intellectual disability, ectodermal abnormalities, congenital heart diseases, chest & skeletal deformity and delayed puberty. During past decades, molecular etiologies of RASopathies have been growingly discovered. The functional perturbations of the RAS-mitogen-activated protein kinase pathway are resulted from the mutation of more than 20 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2, CBL, SOS2, RIT, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, A2ML1, RRAS2). The PTPN11 (40–50%), SOS1 (10–20%), RAF1 (3–17%), and RIT1 (5–9%) mutations are common in NS patients. In this review, the constellation of overlapping clinical features of RASopathies will be described based on genotype as well as their differential diagnostic points and management.
Congenital Abnormalities ; Costello Syndrome ; Diagnosis ; Ectoderm ; Electrocardiography ; Genitalia ; Genotype ; Heart Diseases ; Humans ; Hypertelorism ; Intellectual Disability ; Lentigo ; Noonan Syndrome ; Panthera ; Protein Kinases ; Puberty, Delayed ; Pulmonary Valve Stenosis ; Thorax

OBJECTIVE: To elucidate the association between clinical and laboratory characteristics and pituitary magnetic resonance imaging (MRI) abnormalities in young female patients with hypogonadotropic hypogonadism (HH). METHODS: We retrospectively investigated a series of 74 female patients (age range, 14–42 years) with normoprolactinemic HH who underwent pituitary MRI. Pubertal milestones and hormonal features of patients with small pituitary glands (PGs) and space-occupying lesions were compared with those of patients with normal PGs. RESULTS: The overall frequency of abnormal PGs was 35.1%, with space-occupying lesions observed in 8 patients (10.8%), and small PG observed in 18 patients (24.3%). The mean serum gonadotropin level was not different between patients with and without pituitary MRI abnormalities (P>0.05). Space-occupying lesions were not associated with low gonadotropin levels, type of amenorrhea, or presence of secondary sex characteristics. The frequency of space-occupying lesions was higher in patients with interrupted puberty (25.0%) than in patients who did not go through puberty (4.8%) or had a normal puberty (9.8%), but were not statistically significant (P>0.05). Small PG was associated with low gonadotropin levels and type of amenorrhea (P<0.05). CONCLUSION: Clinically significant space-occupying lesions were not associated with low gonadotropin levels, type of amenorrhea, or presence of secondary sex characteristics. However, the frequency of space-occupying lesions was higher in patients with interrupted puberty than in patients who did not go through puberty or who with normal puberty.
Adolescent ; Amenorrhea ; Female ; Gonadotropins ; Humans ; Hypogonadism ; Magnetic Resonance Imaging ; Pituitary Gland ; Puberty ; Puberty, Delayed ; Retrospective Studies ; Sex Characteristics

The ovarian reserve is necessary for female fertility and endocrine health. Commonly used cancer therapies diminish the ovarian reserve, thus, resulting in primary ovarian insufficiency, which clinically presents as infertility and endocrine dysfunction. Prepubertal children who have undergone cancer therapies often experience delayed puberty or cannot initiate puberty and require endocrine support to maintain a normal life. Thus, developing an effective intervention to prevent loss of the ovarian reserve is an unmet need for these cancer patients. The selection of adjuvant therapies to protect the ovarian reserve against cancer therapies underlies the mechanism of loss of primordial follicles (PFs). Several theories have been proposed to explain the loss of PFs. The “burn out” theory postulates that chemotherapeutic agents activate dormant PFs through an activation pathway. Another theory posits that chemotherapeutic agents destroy PFs through an “apoptotic pathway” due to high sensitivity to DNA damage. However, the mechanisms causing loss of the ovarian reserve remains largely speculative. Here, we review current literature in this area and consider the mechanisms of how gonadotoxic therapies deplete PFs in the ovarian reserve.
Adolescent ; Child ; DNA Damage ; Female ; Fertility ; Fertility Preservation ; Humans ; Infertility ; Ovarian Follicle ; Ovarian Reserve ; Primary Ovarian Insufficiency ; Puberty ; Puberty, Delayed

Mutations in the CHD7 gene, encoding for the chromodomain helicase DNA-binding protein 7, are found in approximately 60% of individuals with CHARGE syndrome (coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities and/or hearing loss). Herein, we present a clinical case of a 14-year-old male presenting for evaluation of poor growth and pubertal delay highlighting the diagnostic challenges of CHARGE syndrome. The patient was born full term and underwent surgery at 5 days of life for bilateral choanal atresia. Developmental milestones were normally achieved. At age 14 his height and weight were
Adolescent ; CHARGE Syndrome ; Choanal Atresia ; Diagnosis ; Ear ; Follicle Stimulating Hormone ; Follow-Up Studies ; Genetic Testing ; Gonadotropins ; Growth and Development ; Hearing ; Heart ; Humans ; Luteinizing Hormone ; Male ; Olfaction Disorders ; Puberty, Delayed ; Testis ; Testosterone

Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty (DP), is mainly found in males, and is characterized by short stature and delayed skeletal maturation. A family history of the subject comprising the timing of puberty in the parents and physical examination may provide clues regarding the cause of DP. Delayed onset of puberty is rarely considered a disease in either sex. In fact, DP usually represents a common normal variant in pubertal timing, with favorable outcomes for final height and future reproductive capacity. In adolescents with CDGP, a linear growth delay occurs until immediately before the start of puberty, then the growth rate rapidly increases. Bone age is often delayed. CDGP is a diagnosis of exclusion; therefore, alternative causes of DP should be considered. Functional hypogonadotropic hypogonadism may be observed in patients with transient delay in hypothalamic-pituitary-gonadal axis maturation due to associated conditions including celiac disease, inflammatory bowel diseases, kidney insufficiency, and anorexia nervosa. Permanent hypogonadotropic hypogonadism (pHH) showing low serum value of testosterone or estradiol and blunted follicle-stimulating hormones (FSH) and luteinizing hormones (LH) levels may be due to abnormalities in the central nervous system. Therefore, magnetic resonance imaging is necessary to exclude morphological abnormalities and neoplasia. Moreover, pHH may be isolated, as observed in Kallmann syndrome, or associated with other hormone deficiencies, as found in panhypopituitarism. Baseline or gonadotropin-releasing hormone pituitary stimulated gonadotropin level is not sufficient to easily differentiate CDGP from pHH. Low serum testosterone in male patients and low estradiol values in female patients, associated with high serum FSH and LH levels, suggest a diagnosis of hypergonadotropic hypogonadism. A genetic analysis can reveal a chromosomal abnormality (e.g., Turner syndrome or Klinefelter syndrome). In cases where the adolescent with CDGP is experiencing psychological difficulties, treatment should be recommended.
Adolescent ; Anorexia Nervosa ; Celiac Disease ; Central Nervous System ; Chromosome Aberrations ; Diagnosis ; Estradiol ; Female ; Gonadotropin-Releasing Hormone ; Gonadotropins ; Humans ; Hypogonadism* ; Inflammatory Bowel Diseases ; Kallmann Syndrome ; Lutein ; Magnetic Resonance Imaging ; Male ; Parents ; Physical Examination ; Puberty ; Puberty, Delayed* ; Renal Insufficiency ; Testosterone ; Turner Syndrome

OBJECTIVES: Mothers who smoke during pregnancy or while their children are small were common in some populations. Epidemiological studies have tried to detect the effect of prenatal tobacco smoke (PTS), and childhood environmental tobacco smoke (ETS) on puberty timing have not shown a consensus results. We aimed to examine current evidence and estimate the associations between PTS or/and ETS and puberty timing. METHODS: Seven databases were searched from inception to May 2017. All the cohort studies examining the associations between PTS and/or ETS and puberty timing were identified. Two reviewers independently screened all studies, evaluated the quality of eligible studies, and extracted the data. The quality assessment of the eligible cohort studies was based on the Newcastle-Ottawa Scale. Risk ratio (RR), standard mean difference (SMD), and 95% confidence intervals (CIs) were calculated and pooled by CMA (Version 2.0, Biostat, Inc., USA). RESULTS: Compared with controls, girls with PTS and ETS exposure have an earlier age at menarche (SMD - 0.087, 95% CI 0.174 to - 0.000), and similar results were found in both PTS subgroup (SMD - 0.097, 95% CI - 0.192 to - 0.002) and prospective cohort subgroup (SMD - 0.171, 95% CI - 0.253 to - 0.090). And number of boys with early voice break in PTS group was significantly increasing than non-exposed boys (RR 1.34, 95% CI 1.29 to 1.40). CONCLUSIONS PTS exposure possibly decrease age of menarche of girls, and studies on boys were urgent needed. Appropriate and comprehensive outcome measures using unified criteria to classify puberty should be reported in future studies.
Aging ; physiology ; Environmental Exposure ; adverse effects ; Female ; Humans ; Menarche ; physiology ; Pregnancy ; Prenatal Exposure Delayed Effects ; etiology ; Puberty ; physiology ; Smoking ; adverse effects ; Tobacco Smoke Pollution ; adverse effects

Noonan syndrome (NS) is a genetic disorder caused by autosomal dominant inheritance and is characterized by a distinctive facial appearance, short stature, chest deformity, and congenital heart disease. In individuals with NS, germline mutations have been identified in several genes involved in the RAS/mitogen-activated protein kinase signal transduction pathway. Because of its clinical and genetic heterogeneity, the conventional diagnostic protocol with Sanger sequencing requires a multistep approach. Therefore, molecular genetic diagnosis using targeted exome sequencing (TES) is considered a less expensive and faster method, particularly for patients who do not fulfill the clinical diagnostic criteria of NS. In this case, the patient showed short stature, dysmorphic facial features suggestive of NS, feeding intolerance, cryptorchidism, and intellectual disability in early childhood. At the age of 16, the patient still showed extreme short stature with delayed puberty and characteristic facial features suggestive of NS. Although the patient had no cardiac problems or chest wall deformities, which are commonly present in NS and are major concerns for patients and clinicians, the patient showed several other characteristic clinical features of NS. Considering the possibility of a genetic disorder, including NS, a molecular genetic study with TES was performed. With TES analysis, we detected a pathogenic variant of c.458A > T in KRAS in this patient with atypical NS phenotype and provided appropriate clinical management and genetic counseling. The application of TES enables accurate molecular diagnosis of patients with nonspecific or atypical features in genetic diseases with several responsible genes, such as NS.
Congenital Abnormalities ; Cryptorchidism ; Diagnosis ; Exome* ; Genetic Counseling ; Genetic Heterogeneity ; Germ-Line Mutation ; Heart Defects, Congenital ; Humans ; Intellectual Disability ; Male ; Methods ; Molecular Biology ; Noonan Syndrome* ; Phenotype ; Protein Kinases ; Puberty, Delayed ; Signal Transduction ; Thoracic Wall ; Thorax ; Wills

PURPOSE: The effects of gonadotropin-releasing hormone agonist (GnRHa) treatment on body mass index (BMI) are controversial in girls with central precocious puberty (CPP). We therefore evaluated auxological parameters during GnRHa therapy in patients with CPP, specifically focusing on changes in BMI. METHODS: Seventy-seven girls with idiopathic CPP who underwent GnRHa therapy were retrospectively recruited. We investigated BMI changes during the treatment period after stratifying them according to baseline BMI status as follows: normal (BMI percentile of <85th) and overweight groups (BMI percentile of ≥85th). RESULTS: The incidence of overweight/obesity (40.3%/23.4%) was very high in the girls with CPP. In the overall study population, no significant BMI change was observed during the GnRHa treatment period. However, when stratified according to baseline BMI status, the normal-weight group showed a significant increase in BMI-standard deviation score (SDS), whereas the overweight group showed no change in BMI-SDS. Baseline BMI-SDS was an independent predictor of changes in BMI during the GnRHa treatment period. Changes in weight-SDS were similar, but changes in height-SDS were significantly greater in the overweight group than in the normal-weight group, which explains the observed difference in BMI-SDS. CONCLUSION: Our results demonstrate that the difference in the pattern of BMI changes among our CPP patients suggests that delayed puberty induced by GnRHa treatment may have different effects on linear growth according to baseline body composition. This study underscores the importance of individualized lifestyle intervention in CPP children.
Body Composition ; Body Mass Index* ; Child ; Female* ; Gonadotropin-Releasing Hormone* ; Humans ; Incidence ; Life Style ; Obesity ; Overweight* ; Puberty, Delayed ; Puberty, Precocious* ; Retrospective Studies