Delayed Puberty.

Testicular volume ≥4 ml and appearance of breast budding are the first signs of puberty. Delayed puberty is diagnosed in the absence of thelarche by 13 y or menarche by 15 y in girls and absence of testicular enlargement by 14 y in boys. Delayed puberty can be due to hypogonadotrophic hypogonadism, hypergonadotrophic hypogonadism or eugonadotrophic eugonadism characterised by low, elevated and normal gonadotrophin levels, respectively. Constitutional Delay of Growth and Puberty (CDGP) and systemic illness should be considered before pathological causes. Assessment of sexual maturity by Tanner's staging and anthropometric assessment on growth chart is pivotal. Lack of menarche in girls with thelarche suggests structural abnormalities of reproductive tract or disorders of sexual development. Measurement of bone age helps to interpret hormone measurements and decide on timing of pubertal induction. Ultrasound assessment of abdomen gives valuable clues to pubertal onset (in girls) and possible underlying etiology. Karyotyping is mandatory in all girls with delayed puberty and short stature, and delayed menarche and boys with hypergonadotrophic hypogonadism. Gonadotrophin releasing hormone analogue stimulation test may help distinguish hypogonadotrophic hypogonadism from CDGP. Pubertal induction is done with intramuscular testosterone and oral estradiol in boys and girls, respectively. Hormone replacement is begun at low doses and slowly escalated over 2 y to mimic a physiological puberty process. Short course of testosterone for 3 to 6 mo is helpful in adolescent boys with CDGP and psychological distress. Attainment of adult sexual maturity by 18 y is mandatory to rule out disorders of hypothalamic pituitary gonadal axis.

Hypogonadism in adolescent girls: treatment and long-term effects.

BACKGROUND AND AIM: Hypogonadism in adolescent females presents as delayed puberty or primary amenorrhea. Constitutional delay of growth and puberty, hypogonadotropic hypogonadism and hypergonadotropic hypogonadism represent the principal differential diagnosis of delayed puberty. Girls with hypogonadism require hormone replacement therapy to initiate and sustain puberty. We aimed to provide a brief review concerning treatment for female adolescents with hypogonadism and further to focus on current data regarding long-term effects of therapy. METHODS: The published studies and articles of the international literature were used regarding the approach to adolescent girls with hypogonadism. RESULTS: The aim of therapy is the development of secondary sexual characteristics and achievement of target height, body composition and bone mass, to promote psychosexual health and, finally, to maximize the potential for fertility. Hypogonadal females need long-term HRT, so it is of great importance to fully define risks and benefits of therapy. CONCLUSIONS: The optimal pubertal induction in women contains both estrogens and progesterone regimens.  Different therapeutic options have been described over the years in the literature, but larger randomized trials are required in order to define the ideal approach. The latest acquisitions in the field seem to propose that transdermal 17ß-estradiol and micronized progesterone present the most physiological formulations available for this purpose. Further studies and follow up are needed concerning the long-term effects of HRT in adolescents.

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

BACKGROUND: 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. OBJECTIVE: To elucidate the role of GnRH agonist-stimulated inhibin B (GnRH-iB) for the differential diagnosis of delayed puberty. STUDY DESIGN: 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. INTERVENTION AND OUTCOME: GnRHa (Triptorelin) stimulation test along with measurement of inhibin B level at 24 h 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 4 h (GnRH-LH) and GnRH-iB were evaluated for the prediction of onset of puberty on prospective follow-up. RESULTS: GnRH-iB at a cut-off value of 113.5 pg/ml in boys and 72.6 pg/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. CONCLUSION: 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 REGISTRATION NO: CTRI/2019/10/021570.

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.

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.

Growth hormone deficiency and other endocrinopathies after childhood brain tumors: results from a close follow-up in a cohort of 242 patients.

PURPOSE: Brain tumors are the most common solid tumor in children. The prevalence of survivors from these cancers has been increasing, presenting endocrine sequelae in more than 40% of the cases. Our aim was to characterize the endocrinopathies diagnosed in this population, exploring the outcomes of growth hormone treatment. METHODS: We have performed a retrospective analysis of the survivors that were followed-up through a close protocol at our endocrine late-effects clinic. RESULTS: 242 survivors, followed during 6.4 (0-23.4) years, were considered. The median age at tumor diagnosis was 6.7 (0-18) years and pilocytic astrocytoma was the most frequent neoplasm (33.5%). The prevalence of endocrinopathies was of 71.5%, with growth hormone deficiency being the most frequent (52.9%). An indirect correlation between the age at the beginning of somatropin and growth velocity in the first year of treatment was observed. Those treated with craniospinal radiotherapy presented a smaller final upper/lower segments ratio comparing with those that only received cranial radiotherapy. However, their final height was not compromised when compared to their family height target. We found pubertal delay in 12%; accelerated/precocious puberty in 13.2%; central and primary hypogonadism in 21.9% and 3.3%, respectively; primary and central hypothyroidism in 23.6% and 14.5%, respectively; thyroid nodules in 7.4%; ACTH deficiency in 10.3% and diabetes insipidus in 12%. CONCLUSION: This study reveals a higher prevalence of endocrinopathies in brain tumors survivors and explores the influence of craniospinal irradiation in the adult body proportions. It reinforces the importance of routine follow-up among survivors.

Phenotype and Natural History of Children With Coexistent Inflammatory Bowel Disease and Celiac Disease.

BACKGROUND: Adult patients with both inflammatory bowel disease (IBD) and celiac disease (CeD) have peculiar phenotypic features. This study aimed at describing the characteristics and natural history of children with both IBD and CeD. METHODS: This was a case-control study based on a national registry. Cases included children diagnosed with both IBD and CeD. Two matched IBD controls without CeD, and 2 matched CeD controls were selected for each case. Inflammatory bowel disease phenotype and natural history, comprising growth and pubertal development, were compared between groups. RESULTS: Forty-nine (1.75%) patients with IBD and CeD were identified out of 2800 patients with IBD. Compared with patients with IBD alone, patients with IBD and CeD presented more frequently with autoimmune diseases (odds ratio, 2.81; 95% CI, 0.97-8.37; P = 0.04). Ileocolonic localization (46.1% vs 73.1%), treatment with azathioprine (46.2% vs 71.2%), and anti-TNF biologics (46.2% vs 69.2%) were less common in patients with Crohn's disease and CeD than in patients with Crohn's disease alone. Patients with ulcerative colitis and CeD had an increased risk of colectomy despite similar medical treatments compared with patients with ulcerative colitis alone (13.0% vs 0%). Pubertal delay was more common in patients with IBD and CeD compared with patients with IBD alone (14.9% vs 3.2%; odds artio, 5.24; 95% CI, 1.13-33.0; P = 0.02) and CeD alone (14.9% vs 1.1%; P = 0.002). CONCLUSIONS: Children with IBD and CeD may have peculiar features with a higher risk for autoimmune diseases, colectomy, and pubertal delay compared with IBD alone.

Non-communicating hydrocephalus with a primary empty sella presenting with growth hormone deficiency and delayed puberty successfully treated by endoscopic third ventriculocisternostomy.

The authors present the unusual case of a 15-year-old boy with a primary empty sella caused by non-communicating hydrocephalus due to fourth ventricle outflow obstruction whose secondary symptoms of growth hormone deficiency and delayed puberty were successfully treated by endoscopic third ventriculocisternostomy (ETV). Hypopituitarism occurs only rarely in cases of hydrocephalus; rarer still are cases where hypopituitarism is the sole symptom of hydrocephalus. A primary empty sella may indicate elevated intracranial pressure; if the cause is non-communicating hydrocephalus, ETV is indicated as the preferred treatment modality.

Eight rare urinary disorders in a patient with Kallmann syndrome: A case report.

RATIONALE: Kallmann syndrome (KS) is a rare inherited genetic disorder characterized by hypogonadotropic hypogonadism and hyposmia/anosmia. Early diagnosis is the key to timely treatment and improvement of prognosis in patients with KS. As the most common complication of KS, renal agenesis can provide clues to early diagnosis and treatment for KS. In this article, we report a case of KS with 8 rare urinary disorders for the first time. PATIENT CONCERNS: A 19-year-old Chinese man presented with 8 rare urinary disorders and a history of bilateral cryptorchidism came to us for micropenis, hyposmia, and delayed puberty. DIAGNOSIS: The patient presented with hyposmia, low levels of sex hormones and showed a weak response to the GnRH stimulation test leading to a diagnosis of KS. Two missense mutations were found in further whole-exome sequencing: 1) Kallmann syndrome 1 (KAL1) gene in exon11, c.1600G > A, p. Val534Ile; 2) Prokineticin receptor 2 (PROKR2) gene in exon 2, c.533G > A, p. Trp178Ser. which led to a diagnosis of KS. INTERVENTIONS: The patient underwent replacement therapy of human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG). The patient had previously undergone six surgeries for cryptorchidism and urinary disorders. OUTCOMES: The patient's puberty retardation was effectively alleviated. His serum testosterone (T) reached a normal level (8.280 nmol/mL). During the follow-up period, he presented with Tanner stage II pubic hair development. CONCLUSION: In this article, we report 8 rare urinary disorders with missense mutations of KAL1 and PROKR2 in a case of KS. Among them, bilateral giant kidneys, urinary extravasation of right renal, bilateral megalo-ureters, left ureteral terminal obstruction, bilateral renal cyst and bladder emptying disorder are reported for the first time, which enrich the integrity of urinary disorder types and provide clues to genetic counseling in patients with KS.

Pubertal outcomes of children transplanted with allogeneic stem cells after myeloablative total body irradiation or busulfan: Influence of age and sex is confirmed, while a role of chronic graft-versus-host disease in delayed puberty onset is revealed.

INTRODUCTION: Myeloablative conditioning before allogeneic HSCT during childhood exposes to serious long-term complications, especially gonadal dysfunction. Pubertal issues are less described than other post-HSCT sequelae in childhood. METHODS: Pubertal development and biological gonadal parameters were assessed in a retrospective monocentric cohort of prepubertal patients who underwent HSCT after myeloablative conditioning with TBI or busulfan between 1981 and 2017. RESULTS: Seventy-four patients (28 girls and 46 boys) were included. No spontaneous pubertal development was found in 50% of girls and 10% of boys (P < .001), and delayed puberty or no spontaneous pubertal development was found in 57% of girls and 24% of boys (P = .009). HRT was used in 82% of girls and 24% of boys (P < .001). In univariate analysis, TBI conditioning (P = .05), female sex (P < .001), acute GVHD (P = .05), extensive chronic GVHD (P = .021), steroid treatment >6 months (P = .016), and malignant diseases (P = .016) were associated with no spontaneous pubertal development, whereas TBI conditioning (P = .003) and extensive chronic GVHD (P = .005) were associated with delayed puberty. In multivariate analysis, factors independently associated with no spontaneous puberty onset were female sex (P = .001) and age >10 years (P = .033). Factors independently associated with delayed puberty were extensive chronic GVHD (P = .041) and age >10 years (P = .031). CONCLUSION: This study highlighted the toxicity of MAC in prepubescent children: TBI did worse, but this was especially true for the most susceptible patients (girls, leukemic patients, and patients older than 10 years). It suggests a possible role of GVHD in delayed puberty.

Unveiling Charles II, the last King of the Habsburg Spanish Empire, in a portrait by Juan Carreño de Miranda (1685).

PURPOSE: Charles II (1661-1700) was the last King of the Habsburg dynasty. He was physically and mentally disabled and died at just 39 years old. Here, the authors attempt to investigate the correlations between his signs and symptoms and the physical appearance on the painting. METHODS: Charles II has been portraited by Juan Carreño de Miranda in a painting that may provide precious information about his premature death. RESULTS: It has been suggested that inbreeding beside other endocrinological disorders were of the major causes responsible for illness and ultimately his death. CONCLUSION: Possible endocrinological diseases have been hypothesized.

Pubertal delay: the challenge of a timely differential diagnosis between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty.

Distinguishing between constitutional delay of growth and puberty (CDGP) and congenital hypogonadotropic hypogonadism (CHH) may be challenging. CDGP and CHH appear to belong to the same clinical spectrum (with low sex hormones and low LH and FSH), although one is classically transient and known as a self-limited form of delayed puberty (CDGP) while the other is permanent (CHH). Thus, the clinical history and the outcomes of these two conditions require different approaches, and an adequate and timely management for the patients is mandatory. Since the initial presentation of CDGP and CHH is almost identical and given the similarities of CDGP and partial forms of CHH (i.e. patients with partial and early interrupted pubertal development) the scientific community has been struggling to find some diagnostic tests able to allow an accurate differential diagnosis between these two conditions in delayed puberty. In this review we provide an up to date insight on the tests available, their meanings and accuracy, as well as some clues to effectively differentiate between constitutional pubertal delay and pathologic CHH.

Introduction to and Screening Visit Results of the Multicenter Pediatric Crohn's Disease Growth Study.

BACKGROUND: Statural growth impairment is more common in males with Crohn's disease (CD). We assessed sex differences in height Z score differences and bone age (BA) Z scores and characterized age of menarche in a novel contemporary cohort of pediatric CD patients undergoing screening for enrollment in the multicenter longitudinal Growth Study. METHODS: Crohn's disease patients (females with chronological age [CA] 5 years and older and younger than 14 years; males with CA 6 years and older and younger than 16 years) participated in a screening visit for the Growth Study. Height BA-Z scores are height Z scores calculated based on BA. Height CA-Z scores are height Z scores calculated based on CA. The height Z score difference equals height CA-Z score minus height BA-Z score. RESULTS: One hundred seventy-one patients (60% male) qualified for this analysis. Mean CA was 12.2 years. Mean height CA-Z score was -0.4, and mean height BA-Z score was 0.4 in females. Mean height CA-Z score was -0.1, and mean height BA-Z score was 0.2 in males. The absolute value of the mean height Z score difference was significantly greater in females (0.8) than males (0.3; P = 0.005). The mean BA-Z score in females (-1.0) was significantly lower than in males (-0.2; P = 0.002). The median CA at menarche was 13.6 (95% CI, 12.6-14.6) years. CONCLUSIONS: Our screening visit data suggest that standardized height gain is lower in males with skeletal maturation and delayed puberty is common in females in CD. We are investigating these findings in the ongoing Growth Study.

A Phenotypic Female Adolescent with Primary Amenorrhea and Dysmorphic Features.

We report on a case of a 14-year-old phenotypic female with a microdeletion at 13q31.1-q31.3, dysmorphic facial and limb features, and neurologic symptoms. She presented to her pediatrician with concerns for delayed puberty, and laboratory analysis revealed hypergonadotropic hypogonadism. She was found to have an XY karyotype and streak gonads. Further genetic studies did not reveal another cause for her gonadal dysgenesis and, to our knowledge, an association with her known 13q-microdeletion has not yet been reported. Given the risk of malignancy with XY gonadal dysgenesis, the patient had surgery to remove the gonads and had no postoperative complications after a 6-month follow-up visit. We also discuss the role of the pediatrician in cases of delayed puberty, from initial diagnosis to definitive management. [Pediatr Ann. 2019;48(12):e495-e500.].

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.

Delayed Puberty-Phenotypic Diversity, Molecular Genetic Mechanisms, and Recent Discoveries.

This review presents a comprehensive discussion of the clinical condition of delayed puberty, a common presentation to the pediatric endocrinologist, which may present both diagnostic and prognostic challenges. Our understanding of the genetic control of pubertal timing has advanced thanks to active investigation in this field over the last two decades, but it remains in large part a fascinating and mysterious conundrum. The phenotype of delayed puberty is associated with adult health risks and common etiologies, and there is evidence for polygenic control of pubertal timing in the general population, sex-specificity, and epigenetic modulation. Moreover, much has been learned from comprehension of monogenic and digenic etiologies of pubertal delay and associated disorders and, in recent years, knowledge of oligogenic inheritance in conditions of GnRH deficiency. Recently there have been several novel discoveries in the field of self-limited delayed puberty, encompassing exciting developments linking this condition to both GnRH neuronal biology and metabolism and body mass. These data together highlight the fascinating heterogeneity of disorders underlying this phenotype and point to areas of future research where impactful developments can be made.

Combined Pituitary Hormone Deficiency Caused by a Synonymous HESX1 Gene Mutation.

CONTEXT: Mutations in the HESX1 gene can give rise to complex phenotypes that involve variable pituitary hormone deficiencies and other developmental defects. CASE DESCRIPTION: A 14-year-old boy presented with short stature and delayed puberty and received a diagnosis of GH deficiency, central hypothyroidism, hypogonadotropic hypogonadism, and secondary adrenal insufficiency. He had anterior pituitary hypoplasia, ectopic posterior pituitary, and an interrupted pituitary stalk. Genetic studies uncovered a heterozygous variant in exon 2 of the HESX1 gene (c.219C>T; p.Ser73Ser). This single base change was predicted to be synonymous at the translational level but was shown to cause skipping of exon 2 in the RNA transcript. CONCLUSIONS: This study of a patient with combined pituitary hormone deficiency revealed an unusual synonymous mutation of the HESX1 gene leading to abnormal RNA processing and indicates the importance of investigating silent variants that at first glance appear to be benign.

[Growth failure as a symptom of inflammatory bowel disease]. / Afbuigende lengtegroeicurve bij inflammatoire darmziekte.

BACKGROUND: Growth failure can be a unique manifestation of untreated intestinal inflammation in children with inflammatory bowel disease (IBD). It can, however, be difficult to diagnose IBD in the absence of symptoms or in the presence of aspecific gastrointestinal symptoms. A delay in diagnosis is a risk factor for lower adult height. CASE DESCRIPTION: A 15--year-old boy was referred to a paediatric endocrinologist for growth failure and delayed puberty. Additional investigations were performed and he was diagnosed with Crohn's disease. CONCLUSION: IBD needs to be considered in a child presenting with growth failure and delayed puberty. A detailed medical history of any gastrointestinal symptoms should be taken. One should perform additional investigations according to the guidelines in a patient who fulfils criteria of short stature.

Delayed Puberty by Ziram Is Associated with Down Regulation of Testicular Phosphorylated AKT1 and SIRT1/PGC-1α Signaling.

Ziram is a dimethyldithiocarbamate fungicide, which may influence the male reproductive system as a potential endocrine disruptor. We interrogated the disruption of ziram on rat progenitor Leydig cell development. Prepubertal male Sprague-Dawley rats were orally treated with 0, 2, 4, or 8 mg/kg ziram for 2 weeks. We investigated the effects of ziram on serum testosterone levels, Leydig cell number, and Leydig and Sertoli cell gene and protein expression, SIRT1/PGC-1α levels, and phosphorylation of AKT1, ERK1/2, and AMPK in vivo. We also interrogated the effects of ziram on reactive oxidative species (ROS) level, apoptosis rate, and mitochondrial membrane potential of progenitor Leydig cells in vitro. Ziram decreased serum testosterone and follicle-stimulating hormone levels, the down-regulated Leydig cell-specific gene ( Lhcgr, Scarb1, Star, Cyp17a1, and Hsd17b3), and their protein expression. However, ziram stimulated anti-Müllerian hormone production. Ziram lowered SIRT1/PGC-1α and phosphorylated protein levels of AKT1. Ziram induced ROS and apoptosis and lowered the mitochondrial membrane potential of progenitor Leydig cells in vitro. In conclusion, ziram disrupts Leydig cell development during the prepubertal period potentially through the SIRT1/PGC-1α and phosphorylated AKT1 signaling.