A novel heterozygous mutation of CHD7 gene in a Chinese patient with Kallmann syndrome: a case report.

BACKGROUND: Variants of chromodomain helicase DNA binding protein 7 (CHD7) gene are commonly associated with Kallmann syndrome (KS) and account for 5-6% of idiopathic hypogonadotropic hypogonadism (IHH) cases. Here we report a novel mutation of CHD7 gene in a patient with KS, which may contribute to the better understanding of KS. CASE PRESENTATION: A 29-year-old male patient with KS and a chief complaint of delayed puberty for 13 years (Tanner B Stage< 4) was admitted to the Department of Endocrinology of the First Affiliated Hospital of Zhejiang University (Hangzhou, China) in September 2019. Dual-energy X-ray absorptiometry (DEXA) showed low bone density in both lumbar spine (L1 ~ L5 mean Z-score - 3.0) and femoral neck (Z-score - 2.7). Dynamic contrast-enhanced magnetic resonance imaging (MRI) of pituitary and contrast-enhanced computed tomography (CT) showed no abnormal findings. Ophthalmological evaluation showed that his both eyes showed exotropia, and no sight loss was noted. Heterozygous c.1619G > T mutation of TCD7 gene (p.G4856V) was detected, whereas none of his family members had this mutation. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) were injected for three times/week to treat idiopathic hypogonadotropic hypogonadism (IHH). After several months of therapy, the patient's health condition improved. His testicles became larger, and his secondary sexual characteristics improved after treatment. CONCLUSION: Exploration of the novel splice-site mutation of CHD7 may further our current understanding of KS.

[Role of health resort factors in the treatment of delayed puberty in teenage girls]. / Rol' sanatorno-kurortnykh faktorov v lechenii zaderzhki polovogo razvitiia u devochek-podrostkov.

Both treatment and effective rehabilitation play an important role in preserving the reproductive health of the girl, the future mother. Along with the search for new drug therapies for various gynecological pathologies, it is important to use physical and natural factors that are natural stimuli for the patient's body. AIM: To examine the effect of health resort factors and methods of physiotherapy on the general condition and hormonal status of girls with delayed sexual development. MATERIAL AND METHODS: 83 patients with delayed sexual development who were examined at the children's clinical sanatorium 'Zdravnitsa' in Yevpatoria (Crimea) were examined: 52 girls were included in the primary group, 31 - in the comparison group. Both groups, depending on age, were divided into subgroups: 13-14 years old and 15-17 years old. Patients in both groups received a standard treatment complex (STC). In addition to SCR, the girls of the main group were prescribed: 5% brine electrophoresis by sinusoidal modulated currents, sage and sea baths. The control group included gynecologic ally healthy adolescents: thirteen 13-14 year-old girls old in the subgroup K1 and twelve 15-17 year-old girls in the subgroup K2. Before and after treatment, all patients underwent standard clinical, gynecological, and laboratory examinations. In both groups, the dynamics of clinical and laboratory parameters, as well as gonadotropic and sex steroid hormones in the blood serum were analyzed. RESULTS: The complex of climatic and physical factors had a nonspecific general stimulating effect. There was a positive dynamics in the general condition of patients, their anthropometric indicators, hormonal status, which was more pronounced in the primary group than in the comparison group. Negative dynamics of the course of diseases in girls of both groups was not observed. CONCLUSION: The use of hardware physiotherapy and sage baths increases the effectiveness of STC. The best clinical and laboratory dynamics of the primary indices was noted in patients 13-14 years old than in patients 15-17 years old. The use of natural and preformed physical factors in treatment makes it possible to minimize the drug effect on the body and achieve the most positive treatment results with a minimum of side effects.

Outcomes and experiences of adults with congenital hypogonadism can inform improvements in the management of delayed puberty.

Patients with congenital hypogonadism will encounter many health care professionals during their lives managing their health needs; from antenatal and infantile periods, through childhood and adolescence, into adult life and then old age. The pubertal transition from childhood to adult life raises particular challenges for diagnosis, therapy and psychological support, and patients encounter many pitfalls. Many patients with congenital hypogonadism and delayed or absent puberty are only diagnosed and treated after long diagnostic journeys, and their management across different centres and countries is not well standardised. Here we reconsider the management of pubertal delay, whilst addressing problematic diagnostic issues and highlighting the limitations of historic pubertal induction protocols - from the perspective of both an adult and a paediatric endocrinologist, dealing in our everyday work with the long-term adverse consequences to our hypogonadal patients of an incorrect and/or late diagnosis and treatment in childhood.

Standard operating procedures: pubertas tarda/delayed puberty--male.

INTRODUCTION: Delayed puberty (DP) is a condition characterized by the lack of sexual maturation in boys (testis volume <4 mL) at a chronological age that is 2.5 standard deviations above the mean age of puberty in a normal population. AIM: To review the etiology, pathogenesis diagnosis, and the available treatments for DP in males. METHODS: A systematic search of published evidence was performed using Medline (1969 to September 2011). MAIN OUTCOME MEASURES: The most important evidence regarding DP and the available treatment options were reviewed and discussed. Whenever possible, levels of evidence are reported. RESULTS: The prevalence of DP in 14-year-old boys in the United States is less than 2%, almost double of same figure in females. The etiology of DP is complex including genetic, functional, or nonidentifiable defects. The correct diagnosis should include an accurate medical history and physical examination along with specific laboratory tests. In addition, bone age radiographs are frequently helpful. If a specific disorder can be identified, therapy should be targeted at that disorder. Short-term testosterone therapy can be offered to boys with constitutional DP after a variable time of expectant observation essentially dictated by the patient's distress. Reassurance and continued observation, to ensure that the expected sexual maturation occurs, are often sufficient. In all other cases, exogenous gonadotropins, either recombinant or extracted, induce full gonadal maturation, while long-term testosterone therapy is the treatment of choice for hypergonadotropic hypogonadism or for hypothalamic or pituitary gonadotropin deficiency until fertility is attained. CONCLUSIONS: DP is a frequent condition that if not correctly diagnosed, may cause serious clinical and psychological consequences. Appropriate diagnosis and treatment provide normal pubertal development.

Detection and management of pediatric conditions that may affect male fertility.

Conditions affecting male fertility may be detected in childhood. Affected children and adolescents and their parents are often anxious and concerned when infertility is discussed. Urology nurses and midlevel providers play a key role in the education and counseling of the patient and family An awareness of the more common conditions, including presentation, evaluation, and management, is critical.

An Approach to the Patient With Delayed Puberty.

Pediatric endocrinologists often evaluate and treat youth with delayed puberty. Stereotypically, these patients are 14-year-old young men who present due to lack of pubertal development. Concerns about stature are often present, arising from gradual shifts to lower height percentiles on the population-based, cross-sectional curves. Fathers and/or mothers may have also experienced later than average pubertal onset. In this review, we will discuss a practical clinical approach to the evaluation and management of youth with delayed puberty, including the differential diagnosis and key aspects of evaluation and management informed by recent review of the existing literature. We will also discuss scenarios that pose additional clinical challenges, including: (1) the young woman whose case poses questions regarding how presentation and approach differs for females vs males; (2) the 14-year-old female or 16-year-old young man who highlight the need to reconsider the most likely diagnoses, including whether idiopathic delayed puberty can still be considered constitutional delay of growth and puberty at such late ages; and finally (3) the 12- to 13-year-old whose presentation raises questions about whether age cutoffs for the diagnosis and treatment of delayed puberty should be adjusted downward to coincide with the earlier onset of puberty in the general population.

Current clinical management of constitutional delay of growth and puberty.

BACKGROUND: Constitutional delay of growth and puberty (CDGP) is classified as the most frequent cause of delayed puberty (DP). Finding out the etiology of DP during first evaluation may be a challenge. In details, pediatricians often cannot differentiate CDGP from permanent hypogonadotropic hypogonadism (PHH), with definitive diagnosis of PHH awaiting lack of puberty by age 18 yr. Neverthless, the ability in providing a precise and tempestive diagnosis has important clinical consequences. MAIN TEXT: A growth failure in adolescents with CDGP may occur until the onset of puberty; after that the growth rate increases with rapidity. Bone age is typically delayed. CDGP is generally a diagnosis of exclusion. Nevertheless, other causes of DP must be evaluated. A family history including timing of puberty in the mother and in the father as well as physical examination may givee information on the cause of DP. Patients with transient delay in hypothalamic-pituitary-gonadal axis maturation due to associated conditions, such as celiac disease, inflammatory bowel diseases, kidney insufficiency and anorexia nervosa, may experience a functional hypogonadotropic hypogonadism. PHH revealing testosterone or estradiol low serum values and reduced FSH and LH levels may be connected to abnormalities in the central nervous system. So, magnetic resonance imaging is required in order to exclude either morphological alterations or neoplasia. If the adolescent with CDGP meets psychological difficulties, treatment is recommended. CONCLUSION: Even if CDGP is considered a variant of normal growth rather than a disease, short stature and retarded sexual development may led to psychological problems, sometimes associated to a poor academic performance. A prompt and precise diagnosis has an important clinical outcome. Aim of this mini-review is throwing light on management of patients with CDGP, emphasizing the adolescent diagnosis and trying to answer all questions from paediatricians.

[Normal puberty and delayed puberty]. / La puberté normale et le retard pubertaire.

Puberty includes important physical and growth changes, and takes place at a certain age range, leading to sexual maturation. Delayed puberty is defined clinically by the absence of breast development after the age of 13,5 in girls, or the absence of increase in testicular size after the age of 14 years in boys. Particularly in boys, delayed puberty, presented as short stature, is a frequent motivation for medical appointment. Constitutional delay of growth and puberty (CDGP) is the most frequent diagnosis ; however, the other etiologies have to be considered. Family history, physical examination including secondary sex characteristics, analysis of growth curve will help to clarify the diagnosis, and may permit avoidance of otherwise evaluations, Adequate work up is important, delayed puberty might lead to psychological difficulties in this context of peer's differences. Even in CDGP, symptomatic treatment with sex steroids might be considered.

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary amenorrhea and female delayed puberty.

Puberty is the period of transition from childhood to adulthood characterized by the attainment of adult height and body composition, accrual of bone strength and the acquisition of secondary sexual characteristics, psychosocial maturation and reproductive capacity. In girls, menarche is a late marker of puberty. Primary amenorrhea is defined as the absence of menarche in ≥ 15-year-old females with developed secondary sexual characteristics and normal growth or in ≥13-year-old females without signs of pubertal development. Furthermore, evaluation for primary amenorrhea should be considered in the absence of menarche 3 years after thelarche (start of breast development) or 5 years after thelarche, if that occurred before the age of 10 years. A variety of disorders in the hypothalamus-pituitary-ovarian axis can lead to primary amenorrhea with delayed, arrested or normal pubertal development. Etiologies can be categorized as hypothalamic or pituitary disorders causing hypogonadotropic hypogonadism, gonadal disorders causing hypergonadotropic hypogonadism, disorders of other endocrine glands, and congenital utero-vaginal anomalies. This article gives a comprehensive review of the etiologies, diagnostics and management of primary amenorrhea from the perspective of pediatric endocrinologists and gynecologists. The goals of treatment vary depending on both the etiology and the patient; with timely etiological diagnostics fertility may be attained even in those situations where no curable treatment exists.

Long-Term Follow-Up and Treatment of a Female With Complete Estrogen Insensitivity.

CONTEXT: We previously reported the first female with a causative ESR1 gene variant, who exhibited absent puberty and high estrogens. At age 15 years, she presented with lower abdominal pain, absent breast development, primary amenorrhea, and multicystic ovaries. The natural history of complete estrogen insensitivity (CEI) in women is unknown. OBJECTIVE: The purpose of this report is to present the neuroendocrine phenotype of CEI, identify potential ligands, and determine the effect of targeted treatment. DESIGN: We have characterized gonadotropin pulsatility and followed this patient's endocrine profile and bone density over 8 years. Seventy-five different compounds were tested for transactivation of the variant receptor. A personalized medicine approach was tailored to our patient. SETTING: Academic medical center. PATIENT OR OTHER PARTICIPANTS: A 24-year-old adopted white female with CEI. INTERVENTION(S): The patient was treated with diethylstilbestrol (DES) for approximately 2.5 years. MAIN OUTCOME MEASURE(S): Induction of secondary sexual characteristics. RESULTS: Luteinizing hormone (LH) pulse studies demonstrated normal pulsatile LH secretion, elevated mean LH, and mildly elevated mean follicle-stimulating hormone (FSH) in the presence of markedly increased estrogens. DES transactivated the variant ESR1 in vitro. However, DES treatment did not induce secondary sexual characteristics in our patient. CONCLUSIONS: Treatment with DES was not successful in our patient. She remains hypoestrogenic despite the presence of ovarian cysts with a hypoestrogenic vaginal smear, absent breast development, and low bone mineral mass. Findings suggest additional receptor mechanistic actions are required to elicit clinical hormone responses.

Disorders of Pubertal Onset.

Evaluation of the child with abnormal pubertal development can be challenging for the primary care provider. Understanding the factors associated with timing of pubertal onset and the normal sequence of pubertal changes is useful in evaluation of children with puberty disorders. A thorough workup includes assessment of growth rate, Tanner staging, and rate of pubertal progression, in addition to an extensive history and physical examination to identify signs and symptoms of disorders associated with abnormal pubertal timing. Initial diagnostic studies will most often include a bone age, levels of gonadotropins, and levels of estradiol (for girls) or testosterone (for boys).

Puberty in cystic fibrosis.

Historically, delayed puberty was considered a common clinical feature of cystic fibrosis (CF). More recent reports have documented normal pubertal progression in the majority of individuals with CF. However, youth with more severe disease are still at risk for delayed puberty. Careful evaluation of pubertal development in children and adolescents with CF is important as pubertal timing impacts linear growth, bone mineral accrual, body image and psychosocial wellbeing, all of which can also be impacted directly by CF. This article reviews the physiology of puberty, timing of puberty in CF, evaluation of pubertal development, and the differential diagnosis, evaluation, and management of delayed and precocious puberty in people with CF.

Constitutional delay of puberty versus congenital hypogonadotropic hypogonadism: Genetics, management and updates.

Delayed puberty (DP) affects approximately 2% of adolescents. In the vast majority of patients in both sexes, it is due to constitutional delay of growth and puberty (CDGP), a self-limited condition in which puberty starts later than usual but progresses normally. However, some CDGP patients may benefit from medical intervention with low-dose sex steroids or peroral aromatase inhibitor letrozole (only for boys). Other causes of DP include permanent hypogonadotropic hypogonadism, functional hypogonadotropic hypogonadism (due to chronic diseases and conditions), and gonadal failure. In this review we discuss these themes along with the latest achievements in the field of puberty research, and include a brief synopsis on the differential diagnosis and management of patients with CDGP and congenital hypogonadotropic hypogonadism.

Delayed Puberty.

Delayed puberty is defined as the absence of physical signs of puberty 2 to 2.5 standard deviations above the mean age and affects approximately 2% of adolescents. Causes of delayed puberty are broadly divided into two categories: hypergonadotropic hypogonadism and hypogonadotropic hypogonadism. One exception to this classification system is constitutional delay of growth and puberty, the most common cause of delayed puberty. For the general pediatrician, knowledge of the different causes and initial steps to evaluation is crucial when a patient with delayed puberty presents. [Pediatr Ann. 2018;47(1):e16-e22.].

Transition of Care from Childhood to Adulthood: Congenital Hypogonadotropic Hypogonadism.

Passage from childhood to adult life involves biological changes culminating in full reproductive capacity as well as psychosocial development. For patients with congenital hypogonadotropic hypogonadism (CHH), this can be an emotionally challenging time as their pubertal failure results in striking physical differences from their peers. CHH is difficult to differentiate from common disorders of puberty such as constitutional delay of growth and puberty. As such, delays in diagnosis are frequent, and it is a common source of stress and frustration for these adolescents. While effective treatments are available for inducing puberty and attaining fertility is possible in most cases, patients may find it difficult to cope with living with CHH. A critical issue for adolescents with CHH is the risk for being lost to follow-up during the transition from pediatric-centered care to adult care. This article will review the state of the art in diagnosis and treatment of patients with CHH with a particular focus on supporting an effective transition from pediatric-centered care to adult-oriented endocrine services. A synthesis of best practices is offered to help guide clinicians in supporting patients and families during this challenging period of care.

Transition in Pediatric and Adolescent Hypogonadal Girls: Gynecological Aspects, Estrogen Replacement Therapy, and Contraception.

Hypogonadism may be suspected if puberty is delayed. Pubertal delay may be caused by a normal physiological variant, by primary ovarian insufficiency (Turner syndrome), or reflect congenital hypogonadotropic hypogonadism (HH; genetic) or acquired HH (brain lesions). Any underlying chronic disease like inflammatory bowel disease, celiac disease, malnutrition (anorexia or orthorexia), or excessive physical activity may also result in functional HH. Thus, girls with delayed puberty should be evaluated for an underlying pathology before any treatment, including oral contraception, is initiated. Estrogen replacement is important and natural 17ß-estradiol, preferably transdermally, is the preferred choice, whereas the oral route can be used as an alternative depending on patient preference and compliance. Sexual activity is often delayed in the hypogonadal adolescent girl. In the adolescent hypogonadal girl, hormone replacement therapy (HRT) most likely has been initiated at the time she becomes sexually active. If a risk of unwanted pregnancy cannot be ruled out, there is a need to consider contraception. This consideration does not contradict the principles of HRT but can be included as a part of the substitution, e.g. oral contraceptives containing 17ß-estradiol or a progestogen intrauterine device combined with continuous 17ß-estradiol (transdermal or oral).