Association between Serum Per- and Polyfluoroalkyl Substance Levels and Risk of Central and Peripheral Precocious Puberty in Girls.

Concerns about the endocrine-disrupting effects of per- and polyfluoroalkyl substances (PFASs) have raised questions about their potential influence on precocious puberty in girls, which is an emerging concern in some populations. However, epidemiological evidence is lacking. In this study, 882 serum samples were collected from girls with central precocious puberty (CPP, n = 226), peripheral precocious puberty (PPP, n = 316), and healthy controls (n = 340) in 2021 in Shanghai, China. The serum levels of 25 legacy and emerging PFASs and 17 steroids were measured. Results showed that PFAS exposure was positively associated with estradiol levels. Eleven PFASs were significantly or marginally associated with the higher odds of the overall precocious puberty. Across subtypes, PFASs were more clearly associated with PPP, while the associations with CPP were consistent in direction but did not reach statistical significance. These findings were consistent with the assessment of PFAS mixtures using quantile-based g-computation (qgcomp) and Bayesian kernel machine regression, with perfluorobutane sulfonate and 6:2 polyfluorinated ether sulfonate showing the highest contribution to joint effects. Although changes in serum estradiol could arise from various factors, our results suggest that the PFAS exposure may contribute to the increase in estradiol secretion, thereby increasing the risk of precocious puberty, especially PPP. The potential effects of PFASs on precocious puberty warrant further investigation, given the associated complications of public health concern, including psychological distress and increased risk of multiple diseases.

Precocious puberty: The clinical profile and the etiological classification of children presented at a tertiary care children's hospital.

Objectives: To determine the clinical spectrum and underlying etiologies of children presented with precocious puberty at The Children's Hospital &The Institute of Child health, Lahore. Methods: It is a retrospective review of all the children presented with precocious puberty over one year, from January 2015 to December 2015; at the department of Paediatric Endocrinology & Diabetes, The Children's Hospital & The Institute of Child Health, Lahore. Results: Total 43 cases of precocious puberty (PP), with 26 females were reported in one year. Central precocious puberty (CPP) constituted 55.8% (24/43) and was found to be more prevalent in female (22/24). In 20/24 cases (83.3%) of central precocious puberty underlying etiology was idiopathic. Peripheral precocious puberty was found in 19/43 cases (44.1%) with male predominance (15/19). Congenital adrenal hyperplasia was the most frequent (12/19) underlying cause of peripheral precocious puberty in our cohort. Conclusion: Precocious puberty could be a manifestation of underlying serious medical condition. It should be thoroughly evaluated with the aim to diagnose the underlying pathology and to treat them promptly.

Diagnosis and management of precocious sexual maturation: an updated review.

The classic definition of precocious sexual maturation is the development of secondary sexual characteristics before 8 years of age in girls and before 9 years of age in boys. It is classified as central precocious puberty when premature maturation of the hypothalamic-pituitary-gonadal axis occurs, and as peripheral precocious puberty when there is excessive secretion of sex hormones, independent of gonadotropin secretion. Precocious sexual maturation is more common in girls, generally central precocious puberty of idiopathic origin. In boys, it tends to be linked to central nervous system abnormalities. Clinical evaluation should include a detailed history and physical examination, including anthropometric measurements, calculation of growth velocity, and evaluation of secondary sexual characteristics. The main sign to suspect the onset of puberty is breast tissue development (thelarche) in girls and testicular enlargement (≥4 mL) in boys. Hormonal assessment and imaging are required for diagnosis and identification of the etiology. Genetic testing should be considered if there is a family history of precocious puberty or other clinical features suggestive of a genetic syndrome. Long-acting gonadotropin-releasing hormone analogs are the standard of care for central precocious puberty management, while peripheral precocious puberty management depends on the etiology.Conclusion: The aim of this review is to address the epidemiology, etiology, clinical assessment, and management of precocious sexual maturation. What is Known: • The main sign to suspect the onset of puberty is breast tissue development (thelarche) in girls and testicular enlargement (≥4 mL) in boys. The classic definition of precocious sexual maturation is the development of secondary sexual characteristics before 8 years of age in girls and before 9 years of age in boys. • Long-acting gonadotropin-releasing hormone agonist (GnRHa) is the standard of care for CPP management, and adequate hormone suppression results in the stabilization of pubertal progression, a decline in growth velocity, and a decrease in bone age advancement. What is New: • Most cases of precocious sexual maturation are gonadotropin-dependent and currently assumed to be idiopathic, but mutations in genes involved in pubertal development have been identified, such as MKRN3 and DLK1. • A different preparation of long-acting GnRHa is now available: 6-month subcutaneous injection.

Peripheral precocious puberty in a girl with an intracranial hCG-producing tumor: case report and literature review.

Human chorionic gonadotropin (hCG)-producing tumors cause peripheral precocious puberty (PP) in boys, but generally not in girls. Homology between LH and hCG activates the LH receptor in testicular Leydig cells, increases testosterone production, and causes virilization. However, since FSH action is required for follicle development, hCG action alone does not increase estradiol (E2) production and does not cause feminization. Only a few cases of peripheral PP with hCG tumors in girls have been reported. We describe the case of a 7-year-old Japanese girl with peripheral PP associated with an hCG-producing tumor. She had prolonged vomiting, loss of appetite, and Tanner stage III breast development. Although no apparent increase in growth rate, bone age was advanced at 9.8 years. Serum E2 was slightly elevated and LH and FSH were below the measurement sensitivity, and abdominal ultrasonography and computed tomography images showed no abnormal findings in the uterus or ovaries. Subsequently, she developed visual field disturbance and loss of consciousness, and brain magnetic resonance imaging revealed an intracranial tumor. Based on pathological findings and abnormally high serum hCG-ß level (48,800 IU/L), intracranial choriocarcinoma was diagnosed. 2.5 months after the start of chemotherapy, the hCG-ß level became almost negative and the breast development disappeared synchronously. Tissue immunostaining of the tumor showed strong positivity for aromatase and hCG, indicating that the choriocarcinoma cells themselves may have produced estrogen via aromatase. This unique case highlights the possibility that hCG-producing tumors can cause peripheral PP in girls as well as boys.

The evaluation of possible role of endocrine disruptors in central and peripheral precocious puberty.

Exposure to environmental chemicals can affect genetic and epigenetic molecular pathways and may cause altered growth and development. Among those exposures, endocrine-disrupting chemicals (EDCs) are of particular concern as humans are abundantly exposed to these chemicals by various means in every period of life. Several well-known environmental chemicals, including phthalates and bisphenol A (BPA), are classified as EDCs. These EDCs are suggested to play roles in early onset of puberty in girls. The aim of this study is to determine plasma phthalate (di(2-ethylhexyl)phthalate [DEHP] and its main metabolite mono(2-ethylhexyl)phthalate [MEHP]) and urinary BPA levels in girls with idiopathic central precocious puberty (CPP) and peripheral precocious puberty (PPP). This study was performed on newly diagnosed idiopathic central precocious puberty (CPP) patients (n = 42) and peripheral precocious puberty (PPP) (n = 42) patients, who were admitted to Keçiören Training and Research Hospital, Clinic of Pediatric Endocrinology between August 2012 and -July 2013. Nonobese healthy girls (n = 50) were used as the control group. Urinary BPA levels were not statistically different in control, PPP and CPP groups (medians 10.91, 10.63 and 10.15 µg/g creatinine, respectively; p > 0.05). Plasma DEHP levels were significantly higher in PPP group when compared to control. Plasma MEHP levels were not significantly different in control and PPP groups (p > 0.05). However, in CPP group, both plasma DEHP and MEHP levels were significantly higher than control and PPP groups. This study showed that phthalates might play a role in the occurence of CPP in girls.

[Peripheral precocious puberty]. / Periferní predcasná puberta (pseudopubertas praecox).

OBJECTIVE: To summarize literature data on peripheral precocious puberty. DESIGN: A literature review. SETTING: Stredomoravská nemocnicní a.s., hospital Sternberk, Department of Obstetrics and Gynaecology, University Hospital, Medical Faculty, Palacky University, Olomouc. METHODS AND RESULTS: We searched in PubMed using the key words stated below according to date and published since 1980.Peripheral precocious puberty occurs in girls with the frequency 1:400-1000. It develops mainly because of peripheral estrogen secretion, the main cause of which are autonomous ovarian cysts. Other causes include McCune Albright syndrome, juvenile granulosa cell tumor and primary hypothyroidism. Typically, peripheral precocious puberty presents with early breast enlargement followed by development of other secondary sex characteristics. Initial treatment is usually conservative with the exception of juvenile granulosa cell tumor where surgery is warranted. Peripheral precocious puberty anti-estrogen therapy seems promising but neither data on its influence on fertility nor data comparing it to surgical treatment are available. Due to the risk of progression into central precocious puberty or McCune Albright syndrome, long-term follow-up is necessary. CONCLUSION: Peripheral precocious puberty should be managed in pediatric gynecology outpatient office and often subsides spontaneously. However, it can also be a sign of malignancy. In most cases, conservative therapy is preferred with medical treatment and surgery warranted in complicated cases. However, optimal treatment has not been established yet.

Vaginal bleeding imitated rape in a 6-year old girl, a case report about granulosa cell tumor as a reason of peripheral precocious puberty.

INTRODUCTION: Although female victims of sexual child abuse present with symptoms such as local pain and vaginal bleeding, however, before any definitive diagnosis a comprehensive physical examination along with a detailed history related to vaginal bleeding should be taken from the patient. Undoubtedly, we must not forget that only one of the causes of vaginal bleeding is rape. Therefore, before making a final diagnosis, other causes of this symptom must be carefully examined. CASE PRESENTATION: The patient was a 6-years-old female who was hospitalized for notable generalized abdominal distention, acute lower abdomen pain associated with nausea and mild fever lasting 5 days progressively worsening, thelarche and vaginal bleeding. Ultrasound examination showed that multilocular-solid masses located in right side of abdomen which led to surgery and mass excision. Histopathology diagnosis was a juvenile granulosa cell tumor of the ovary. DISCUSSION: Among the various causes of peripheral premature puberty, granulosa cell tumor (GCT) is rare but very important. Since in the two age groups - prepuberty and menopause - we don't expect to see vaginal bleeding, the occurrence of this disorder especially in association with breast enlargement in prepubertal group, need to appropriate imaging including pelvic ultrasound and bone age determination also laboratory data such as level of sex hormones and tumor markers to avoid misdiagnosis. CONCLUSION: We report the case of a granulosa cell tumor patient with vaginal bleeding that a complete history and examination provides the right path to a diagnosis.

Heterozygous gain of function variant in GUCY1A2 may cause autonomous ovarian hyperfunction.

PURPOSE: The purpose of this study was to characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene. METHODS: An individual carrying the de novo heterozygous variant c.1458G>T p.(E486D) in GUCY1A2 was identified by exome sequencing. The effect of the corresponding enzyme variant α2E486D/ß1 was evaluated using concentration-response measurements with wild-type enzyme and the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged constructs by confocal laser scanning microscopy. RESULTS: The patient presented with precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright syndrome. Additionally, the patient displayed severe intellectual disability. In vitro activity assays revealed an increased nitric oxide affinity for the mutant enzyme. The response to carbon monoxide was unchanged, while thermostability was decreased compared to wild type. Heme content, susceptibility to oxidation, and subcellular localization upon overexpression were unchanged. CONCLUSION: Our data define a syndromic autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2 leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary. Additional cases will be needed to ensure a causal link.

Diagnosis of Central Precocious Puberty.

A thorough history and physical examination including Tanner staging and growth assessments can guide differential diagnosis and aid in the evaluation of precocious puberty. Basal luteinizing hormone levels measured using a highly sensitive assay can be helpful in diagnosing central precocious puberty (CPP). Brain MRI is indicated with males diagnosed with CPP and females under the age of 6 with CPP. As more information becomes available regarding the genetic etiologies of CPP, genetic testing may preclude the need for imaging studies and other hormonal testing, especially in familial cases.

Presentation and Care for Children with Peripheral Precocious Puberty.

Peripheral precocious puberty (PPP) refers to the early onset of sexual maturation that is independent of central nervous system control. The extensive differential diagnosis includes congenital and acquired causes. Presenting features depend on which class of sex steroids is involved, and diagnosis rests on hormonal and, if indicated, imaging and/or genetic studies. Effective treatment exists for nearly all causes of PPP. Ongoing research will advance our therapeutic armamentarium and understanding of the pathophysiologic basis of these conditions.

Human chorionic gonadotrophin secreting adrenocortical neoplasm presenting with peripheral precocious puberty in an infant.

Adrenocortical tumor (ACT) is a rare malignant tumor which usually present with Cushing syndrome and virilization. Paraneoplastic syndromes (PNS) due to neoplasms can occur with peptides or cytokines secreted by the tumor. Here, we report a 13-month-old-male presented with severe masculinization. He had signs of precocious puberty with enlarged testicles, very high testosterone levels but low levels of gonadotrophins, and elevated ß-hCG. He underwent a left nephrectomy. The histopathological evaluation revealed a diagnosis of adrenocortical neoplasm. The levels of androgens and ß-hCG normalized after the resection of tumor, and the clinical findings improved within few months. We report the first pediatric patient with peripheral precocious puberty due to an ACT that secretes ß-hCG as PNS. A ß-hCG secreting ACT can cause severe virilization due to increased gonadal androgens stimulated by ß-hCG as well as due to increased adrenal androgens from the tumor.

Peripheral precocious puberty in Li-Fraumeni syndrome: a case report and literature review of pure androgen-secreting adrenocortical tumors.

INTRODUCTION: Pure androgen-secreting adrenocortical tumors are a rare but important cause of peripheral precocious puberty. CASE PRESENTATION: Here, we report a pure androgen-secreting adrenocortical tumor in a 2.5-year-old boy presenting with penile enlargement, pubic hair, frequent erections, and rapid linear growth. We confirmed the diagnosis through laboratory tests, medical imaging, and histology. Furthermore, genetic testing detected a pathogenic germline variant in the TP53 gene, molecularly confirming underlying Li-Fraumeni syndrome. DISCUSSION: Only 15 well-documented cases of pure androgen-secreting adrenocortical tumors have been reported so far. No clinical or imaging signs were identified to differentiate adenomas from carcinomas, and no other cases of Li-Fraumeni syndrome were diagnosed in the four patients that underwent genetic testing. However, diagnosing Li-Fraumeni syndrome is important as it implies a need for intensive tumor surveillance and avoidance of ionizing radiation. CONCLUSION: In this article, we emphasize the need to screen for TP53 gene variants in children with androgen-producing adrenal adenomas and report an association with arterial hypertension.

A Case of Peripheral Precocious Puberty May Be Caused by a Diet Containing Phytosterols in a 20-Month-Old Boy.

INTRODUCTION: Precocious puberty in boys generally remains an etiology. In addition to the causes of endogenous hormone changes, endocrine-disrupting chemicals of exogenous substances may interfere with children's pubertal development. CASE PRESENTATION: A 20-month-old boy presented with peripheral precocious puberty may be due to a phytosterol-containing diet. The patient came to see a doctor because of acne, hairiness, increased penis size, and coarse voice. Genital examination revealed a Tanner stage of 2 for pubic hair and a stretched penile length of 5 cm, which disagreed with the prepubertal testicular volume (2 mL bilaterally). At the same time, he was found to have pigmentation on both nipples and areola. The concentrations of estradiol and testosterone increased significantly. Since the age of 6 months, the patient had taken food added with a large amount of chicken essence seasoning (a flavoring in Chinese cooking), with an average of 15 g of this seasoning a day. A kind of phytosterol (C29H48O) was detected in chicken essence seasoning by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). After avoidance of the chicken essence seasoning, the patient's sex hormone levels decreased, all clinical symptoms returned to normal, and no further development of secondary sexual characteristics was detected. CONCLUSION: This phytosterol-containing diet may be responsible for the sexual development of this patient. However, the mechanism of how phytosterols affect the process of development in children needs to be further explored.

Familial Male-limited Precocious Puberty (FMPP) and Testicular Germ Cell Tumors.

OBJECTIVE: The purpose of this study is to report development of a malignant testicular germ cell tumor (GCT) in 2 young adult males with familial male-limited precocious puberty (FMPP) because of LHCGR pathogenic variants in 2 families. Secondarily, to study the possible relation between FMPP and testicular tumors and to investigate whether FMPP might predispose to development of malignant testicular tumors in adulthood a literature review is conducted. METHODS: Data on 6 cases in 2 families are obtained from the available medical records. In addition, a database search is performed in Cochrane, PubMed, and Embase for studies that report on a possible link between FMPP and testicular tumors. RESULTS: The characteristics of 6 males with FMPP based on activating LH receptor (LHCGR) germline pathogenic variants are described, as are details of the testicular GCTs. Furthermore, a literature review identified 4 more patients with signs of FMPP and a (precursor of) testicular GCT in adolescence or adulthood (age 15-35 years). Additionally, 12 patients with signs of precocious puberty and, simultaneously, occurrence of a Leydig cell adenoma or Leydig cell hyperplasia are reported. CONCLUSION: There is a strong suggestion that FMPP might increase the risk of development of testicular GCTs in early adulthood compared with the risk in the general population. Therefore, prolonged patient monitoring from mid-pubertal age onward including instruction for self-examination and periodic testicular ultrasound investigation in patients with a germline LHCGR pathogenic variant might contribute to early detection and thus early treatment of testicular GCT.

Rapidly Progressive Precocious Puberty With an Elevated Testosterone Level in a 5-Year-Old Boy With a ß-Human Chorionic Gonadotropin-Secreting Intracranial Germ Cell Tumor in the Pineal Gland.

Objective: Peripheral precocious puberty (PP) is an infrequent etiology for early sexual development. Intracranial germ cell tumors (GCTs) are rare but can present infrequently with PP with the rate of development affected by the degree of tumor hormone production. Our objective was to describe a young boy with a ß-human chorionic gonadotropin (hCG)-secreting intracranial GCT with an extremely elevated testosterone level, who presented with rapidly progressive PP. Case Report: A 5-year-old boy presented with penile growth plus pubic hair, deepening voice, and body odor for 3 months. Physical examination revealed a height velocity of 16.25 cm/year, Tanner stage 3 pubic hair, and enlarged penis for age. Laboratory results revealed elevated serum and cerebrospinal fluid ß-hCG and 17-hydroxyprogesterone progesterone levels. The testosterone level was above the initial detection range at 2700 ng/dL. Follicle-stimulating hormone and luteinizing hormone were prepubertal with normal serum and cerebrospinal fluid alpha-fetoprotein levels. Imaging showed a pineal mass diagnosed as a ß-hCG-secreting GCT. During chemotherapy, the physical signs of PP remitted and laboratory values normalized. Discussion: Intracranial tumors can cause peripheral PP in boys. If the tumor produces high ß-hCG levels, this could cause severe hyperandrogenemia resulting in the rapid development of secondary sexual signs. GCTs should be considered in male patients with rapidly progressive PP, even in those lacking other signs of a brain tumor. Conclusion: When presented with a boy with PP, a GCT should be considered if workup shows an elevated testosterone level in conjunction with an elevated ß-hCG level, especially if with rapid development.

Delayed and Precocious Puberty: Genetic Underpinnings and Treatments.

Delayed puberty may signify a common variation of normal development, or indicate the presence of a pathologic process. Constitutional delay of growth and puberty is a strongly familial type of developmental pattern and accounts for the vast majority of children who are "late bloomers." Individuals with sex chromosomal abnormalities frequently have hypergonadotropic hypogonadism. There are currently 4 known monogenic causes of central precocious puberty. The primary treatment goal in children with hypogonadism is to mimic normal pubertal progression, while the primary aims for the management of precocious puberty are preservation of height potential and prevention of further pubertal development.

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).

Peripheral precocious puberty including congenital adrenal hyperplasia: causes, consequences, management and outcomes.

Peripheral precocious puberty results from peripheral production of sex steroids independent of activation of the hypothalamic-pituitary gonadal axis. It is much less common than central precocious puberty. Causes are variable and can be congenital or acquired. In this review, we will discuss the diagnosis and management of the most common etiologies including congenital adrenal hyperplasia, McCune Albright syndrome, familial male-limited precocious puberty, and adrenal and gonadal tumors.

Phenotypic testicular abnormalities and pubertal development in boys with McCune-Albright syndrome.

Aim of this survey is to review the few available literature data on pathophysiologic and clinical aspects of pubertal development in boys with McCune-Albright syndrome (MAS). On the basis of such analysis, we concluded that:1) peripheral precocious puberty (PPP) is significantly more infrequent in boys than in girls; 2) the most common testicular abnormality at MAS presentation is macroorchidism, that may be either monolateral or bilateral; 3) macroorchidism is not always associated with clinical and biochemical evidence of PPP; 4) testicular microlothiasis is distinctly more frequent in boys with MAS than in those without MAS; 5) the available therapeutic schedules have to be adopted already at MAS presentation only in the cases with PPP.

Peculiarities of Precocious Puberty in Boys and Girls With McCune-Albright Syndrome.

McCune-Albright Syndrome (MAS; OMIM # 174800) is a rare, sporadic disease caused by a post-zygotic, activating mutation in the guanine-nucleotide binding protein α-subunit (GNAS1) gene. MAS is characterized by the clinical triad of polyostotic fibrous dysplasia of bone, café-au-lait skin pigmentation and peripheral precocious puberty. However, clinical presentation is highly variable depending on mosaic tissue distribution of mutant-bearing cells. Precocious puberty is the most common endocrine manifestation of MAS and is often the presenting, and sometimes the only, clinical sign of MAS. Due to the very low prevalence of MAS, data on course of precocious puberty, effectiveness of treatments and gonadal function during post-pubertal period are lacking. Our knowledge on this issue derives essentially from case reports and small cohorts of patients. The aim of this review is to report all available literature data on clinical aspects, therapeutic management and outcomes of precocious puberty in children with MAS. A systematic research was carried out through MEDLINE via PubMed, EMBASE, Web of Science, Semantic Scholar, Cochrane Library.